Muddy's grandmother, Della Grant, raised him after his mother died shortly following his birth. Della gave the boy the nickname "Muddy" at an early age because he loved to play in the muddy water of nearby Deer Creek. Muddy later changed it to "Muddy Water" and finally "Muddy Waters".

The shack where Muddy Waters lived in his youth on Stovall Plantation is now located at the Delta Blues Museum in Clarksdale, Mississippi. He started out on harmonica, but by age seventeen he was playing the guitar at parties, emulating two blues artists who were extremely popular in the south, Son House and Robert Johnson.

On November 20, 1932, Muddy married Mabel Berry; Robert Nighthawk played guitar at the wedding, and the party reportedly got so wild the floor fell in. Mabel left Muddy three years later when Muddy's first child was born; the child's mother was Leola Spain, sixteen years old (Leola later used her maiden name Brown), "married to a man named Steven" and "going with a guy named Tucker". Leola was the only one of his girlfriends with whom Muddy would stay in touch throughout his life; they never married. By the time he finally cut out for Chicago in 1943, there was another Mrs. Morganfield left behind, a girl called Sallie Ann.

In 1940 Muddy moved to Chicago for the first time. He played with Silas Green a year later, and then returned to Mississippi. In the early part of the decade he ran a juke joint, complete with gambling, moonshine, and a jukebox; he also performed music there himself. In the summer of 1941, Alan Lomax went to Stovall, Mississippi, on behalf of the Library of Congress, to record various country blues musicians. "He brought his stuff down and recorded me right in my house," Muddy recalled in Rolling Stone, "and when he played back the first song I sounded just like anybody's records. Man, you don't know how I felt that Saturday afternoon when I heard that voice and it was my own voice. Later on he sent me two copies of the pressing and a check for twenty bucks, and I carried that record up to the corner and put it on the jukebox. Just played it and played it and said, 'I can do it, I can do it.'" Lomax came back in July 1942 to record Muddy again. Both sessions were eventually released as Down On Stovall's Plantation on the Testament label. The complete recordings were re-issued on CD as Muddy Waters: The Complete Plantation Recordings. The historic 1941-42 Library of Congress field recordings by Chess Records in 1993, and re-mastered in 1997.

In 1943, Muddy headed back to Chicago with the hope of becoming a full-time professional musician. He lived with a relative for a short period while driving a truck and working in a factory by day and performing at night. Big Bill Broonzy, then one of the leading bluesmen in Chicago, helped Muddy break into the very competitive market by allowing him to open for his shows in the rowdy clubs. In 1945, Muddy's uncle, Joe Grant, gave him his first electric guitar, which enabled him to be heard above the noisy crowds.

In 1946, he recorded some tunes for Mayo Williams at Columbia but they were not released at the time. Later that year he began recording for Aristocrat Records, a newly-formed label run by two brothers, Leonard and Phil Chess. In 1947, he played guitar with Sunnyland Slim on piano on the cuts "Gypsy Woman" and "Little Anna Mae." These were also shelved, but in 1948, "I Can't Be Satisfied" and "I Feel Like Going Home" became big hits and his popularity in clubs began to take off. Soon after, Aristocrat changed their label name to Chess Records and Muddy's signature tune "Rollin' Stone" also became a smash hit.

Initially, the Chess brothers would not allow Muddy to use his own guitar in the recording studio; instead he was provided with a backing bass by Ernest "Big" Crawford, or by musicians assembled specifically for the recording session, including "Baby Face" Leroy Foster and Johnny Jones. Gradually Chess relented, and by September 1953 he was recording with one of the most acclaimed blues groups in history: Little Walter Jacobs on harmonica, Jimmy Rogers on guitar, Elga Edmonds (a.k.a. Elgin Evans) on drums and Otis Spann on piano. The band recorded a series of blues classics during the early 1950s, some with the help of bassist/songwriter Willie Dixon, including "Hoochie Coochie Man" (Number 8 on the R&B charts), "I Just Want to Make Love to You" (Number 4), and "I'm Ready". These three were "the most macho songs in his repertoire," wrote Robert Palmer in Rolling Stone. "Muddy would never have composed anything so unsubtle. But they gave him a succession of showstoppers and an image, which were important for a bluesman trying to break out of the grind of local gigs into national prominence." Along with his former harmonica player Little Walter Jacobs and recent southern transplant Howlin' Wolf, Muddy reigned over the early 1950s Chicago blues scene, his band becoming a proving ground for some of the city's best blues talent. While Little Walter continued a collaborative relationship long after he left Muddy's band in 1952, appearing on most of Muddy's classic recordings throughout the 1950s, Muddy developed a long-running, generally good-natured rivalry with Wolf. The success of Muddy's ensemble paved the way for others in his group to break away and enjoy their own solo careers. In 1952 Little Walter left when his single "Juke" became a hit, and in 1955 Rogers quit to work exclusively with his own band, which had been a sideline until that time. Although he continued working with Muddy's band, Otis Spann enjoyed a solo career and many releases under his own name beginning in the mid-1950s. Around that time, Muddy Waters scored hits with the rock songs "Mannish Boy" and "Sugar Sweet" in 1955, followed by the R&B hits "Trouble No More," "Forty Days & Forty Nights" and "Don't Go No Farther" in 1956.

Muddy headed to England in 1958 and shocked audiences (whose only previous exposure to blues had come via the acoustic folk/blues sounds of acts such as Sonny Terry and Brownie McGhee and Big Bill Broonzy) with his loud, amplified electric guitar and thunderous beat. His performance at the 1960 Newport Jazz Festival, recorded and released as his first live album, At Newport 1960, helped turn on a whole new generation to Muddy's sound. He expressed dismay when he realized that members of his own race were turning their backs on the genre while a white audience had shown increasing respect for the blues.

However, for the better part of twenty years (since his last big hit in 1956, "I'm Ready") Muddy was put on the back shelf by the Chess label and recorded albums with various "popular" themes: Brass And The Blues, Electric Mud, etc. In 1967, he joined forces with Bo Diddley, Little Walter and Howlin' Wolf to record the Super Blues and The Super Super Blues Band pair of albums of Chess blues standards. In 1972 he went back to England to record The London Muddy Waters Sessions with Rory Gallagher, Steve Winwood, Rick Grech and Mitch Mitchell — but their playing was not up to his standards. "These boys are top musicians, they can play with me, put the book before 'em and play it, you know," he told Guralnick. "But that ain't what I need to sell my people, it ain't the Muddy Waters sound. An' if you change my sound, then you gonna change the whole man."

Muddy's sound was basically Delta blues electrified, but his use of microtones, in both his vocals and slide playing, made it extremely difficult to duplicate and follow correctly. "When I play on the stage with my band, I have to get in there with my guitar and try to bring the sound down to me. But no sooner than I quit playing, it goes back to another, different sound. My blues look so simple, so easy to do, but it's not. They say my blues is the hardest blues in the world to play."

Muddy's long-time wife Geneva died of cancer on March 15, 1973. A devastated Muddy was taken to a doctor and told to quit smoking, which he did. Gaining custody of some of his "outside kids", he moved them into his home, eventually buying a new house in Westmont, Illinois. Another teenage daughter turned up while on tour in New Orleans; Big Bill Morganfield was introduced to his Dad after a gig in Florida. Florida was also where Muddy met his future wife, the 19-year-old Marva Jean Brooks whom he nicknamed "Sunshine".

On November 25, 1976, Muddy Waters performed at The Band's farewell concert at Winterland in San Francisco. The concert was released as both a record and a film, The Last Waltz, featuring a performance of "Mannish Boy" with Paul Butterfield on harmonica.

In 1977 Johnny Winter convinced his label, Blue Sky, to sign Muddy, the beginning of a fruitful partnership. His "comeback" LP, Hard Again, was recorded in just two days and was a return to the original Chicago sound he had created 25 years earlier, thanks to Winter's production. Former sideman James Cotton contributed harmonica on the Grammy Award winning album and a brief tour followed.

The Muddy Waters Blues Band at the time included guitarists Sammy Lawhorn, Bob Margolin and Luther "Snake Boy" Johnson, pianist Pinetop Perkins, harmonica player Jerry Portnoy, bassist Calvin "Fuzz" Jones and drummer Willie "Big Eyes" Smith. On "Hard Again", Winter played guitar in addition to producing; Muddy asked James Cotton to play harp on the session, and Cotton brought his own bassist Charles Calmese. According to Margolin's liner notes, Muddy did not play guitar during these sessions. The album covers a broad spectrum of styles, from the opening of "Mannish Boy", with shouts and hollers throughout, to the old-style Delta blues of "I Can't Be Satisfied", with a National Steel solo by Winter, to Cotton's screeching intro to "The Blues Had a Baby", to the moaning closer "Little Girl". Its live feel harks back to the Chess Records days, and it evokes a feeling of intimacy and cooperative musicianship. The expanded reissue includes one bonus track, a remake of the 1950s single "Walking Through the Park". The other outtakes from the album sessions appear on King Bee. Margolin's notes state that the reissued album was remastered but that remixing was not considered to be necessary. Hard Again was the first studio collaboration between Muddy and Winter, who produced his final four albums, the others being I'm Ready, King Bee, and Muddy "Mississippi" Waters - Live, for Blue Sky, a Columbia Records subsidiary.

In 1978, Winter recruited two of Muddy's cohorts from the early 1950s, Big Walter Horton and Jimmy Rogers, and brought in the rest of his touring band at the time (harmonica player Jerry Portnoy, guitarist Luther "Guitar Junior" Johnson, and bassist Calvin "Fuzz" Jones) to record I'm Ready which came close to the critical and commercial success of Hard Again.

The comeback continued in 1979 with the lauded LP Muddy "Mississippi" Waters Live. "Muddy was loose for this one," wrote Jas Obrecht in Guitar Player, "and the result is the next best thing to being ringside at one of his foot-thumping, head-nodding, downhome blues shows." On the album, Muddy is accompanied by his touring band, augmented by Johnny Winter on guitar. The set list contains most of his biggest hits, and the album has an energetic feel. King Bee the following year concluded Waters' reign at Blue Sky, and these last four LPs turned out to be his biggest-selling albums ever. King Bee was the last album Muddy Waters recorded. Coming last in a trio of studio outings produced by Johnny Winter, it is also a mixed bag. During the sessions for King Bee, Muddy, his manager and his band were involved in a dispute over money. According to the liner notes by Bob Margolin, the conflict arose from Muddy's health being on the wane and consequently playing fewer engagements. The bandmembers wanted more money for each of the fewer gigs they did play in order to make ends meet. Ultimately a split occurred and the entire band quit. Because of the tensions in the studio preceding the split, Winter felt the sessions had not produced enough solid material to yield an entire album, and filled out King Bee with outtakes from earlier Blue Sky sessions. The cover photograph is by David Michael Kennedy. For the listener, King Bee is a leaner and meaner record. Less of the good-time exuberance present on the previous two outings is present here. The title track, "Mean Old Frisco", "Sad Sad Day", and "I Feel Like Going Home", are all blues with ensemble work. The Sony Legacy issue features completely remastered sound and Margolin's notes, and also hosts two bonus tracks from the King Bee sessions that Winter did not see fit to release the first time.

In 1981, Muddy Waters was invited to perform at ChicagoFest, the city's top outdoor music festival. He was joined onstage by Johnny Winter—who had successfully produced his most recent albums—and played classics like "Mannish Boy," "Trouble No More" and "Mojo Working" to a new generation of fans. This historic performance was made available on DVD in 2009 by Shout! Factory. Later that year, Waters performed live with the Rolling Stones at the Checkerboard Lounge, with a DVD version of the concert released in 2012.

In 1982, declining health dramatically curtailed Muddy's performance schedule. His last public performance took place when he sat in with Eric Clapton's band at a Clapton concert in Florida in autumn of 1982.

On April 30, 1983 Muddy Waters died in his sleep from heart failure, at his home in Westmont, Illinois. At his funeral at Restvale Cemetery in Alsip, Illinois, throngs of blues musicians and fans showed up to pay tribute to one of the true originals of the art form. "Muddy was a master of just the right notes," John P. Hammond, told Guitar World magazine. "It was profound guitar playing, deep and simple... more country blues transposed to the electric guitar, the kind of playing that enhanced the lyrics, gave profundity to the words themselves." Two years after his death, Chicago honored him by designating the one-block section between 900 and 1000 E. 43rd Street near his former home on the south side "Honorary Muddy Waters Drive". The Chicago suburb of Westmont, where Muddy lived the last decade of his life, named a section of Cass Avenue near his home "Honorary Muddy Waters Way". Following his death, fellow blues musician B.B. King told Guitar World, "It's going to be years and years before most people realize how greatly he contributed to American music". A Mississippi Blues Trail marker has been placed in Clarksdale, Mississippi by the Mississippi Blues Commission designating the site of Muddy Waters' cabin.

His influence is tremendous, over a variety of music genres: blues, rhythm and blues, rock 'n' roll, hard rock, folk, jazz, and country. He also helped Chuck Berry get his first record contract.

His 1958 tour of England marked possibly the first time amplified, modern urban blues was heard there, although on his first tour he was the only one amplified. His backing was provided by Englishman Chris Barber's trad jazz group. (One critic retreated to the toilets to write his review because he found the band so loud).

The Rolling Stones named themselves after his 1950 song "Rollin' Stone" (also known as "Catfish Blues", which Jimi Hendrix covered as well). Hendrix recalled "the first guitar player I was aware of was Muddy Waters. I first heard him as a little boy and it scared me to death". Cream covered "Rollin' and Tumblin'" on their 1966 debut album Fresh Cream, as Eric Clapton was a big fan of Muddy Waters when he was growing up, and his music influenced Clapton's music career. The song was also covered by Canned Heat at the legendary Monterey Pop Festival and later adapted by Bob Dylan on the album Modern Times. One of Led Zeppelin's biggest hits, "Whole Lotta Love", is lyrically based upon the Muddy Waters hit "You Need Love", written by Willie Dixon. Dixon wrote some of Muddy Waters' most famous songs, including "I Just Want to Make Love to You" (a big radio hit for Etta James, as well as the 1970s rock band Foghat), "Hoochie Coochie Man", which The Allman Brothers Band famously covered (the song was also covered by Humble Pie and Steppenwolf), and "I'm Ready". In 1993, Paul Rodgers released the album Muddy Water Blues: A Tribute to Muddy Waters, on which he covered a number of Muddy Waters songs, including "Louisiana Blues", "Rollin' Stone", "Hoochie Coochie Man" and "I'm Ready" (among others) in collaboration with a number of famous guitarists such as Gary Moore, Brian May and Jeff Beck.

Angus Young of the rock group AC/DC has cited Muddy Waters as one of his influences. The AC/DC song title "You Shook Me All Night Long" came from lyrics of the Muddy Waters song "You Shook Me", written by Willie Dixon and J. B. Lenoir. Earl Hooker first recorded it as an instrumental which was then overdubbed with vocals by Muddy Waters in 1962. Led Zeppelin also covered it on their debut album.

Muddy Waters' songs have been featured in long-time fan Martin Scorsese's movies, including The Color of Money, Goodfellas and Casino. Muddy Waters' 1970s recording of his mid-'50s hit "Mannish Boy" (a.k.a. "I'm A Man") was used in Goodfellas and the hit film Risky Business, and also features in the rockumentary The Last Waltz.

The song "Come Together" by The Beatles references Muddy Waters: "He roller coaster/he got Muddy Waters."

American Stoner Metal band Bongzilla covered Muddy Water's song Champagne and Reefer on their album Amerijuanican.

The 2006 Family Guy episode "Saving Private Brian" includes a parody of Muddy Waters trying to pass a kidney stone; his screams of pain form a call and response with the Chicago blues band in his bathroom.

In 2008, Jeffrey Wright portrayed Muddy in the biopic Cadillac Records, a film about the rise and fall of Chess Records and the lives of its recording artists. A second 2008 film about Leonard Chess and Chess Records, Who Do You Love, also covers Muddy's time at Chess Records.

In the 2009 film The Boat that Rocked (retitled Pirate Radio in the U.S) about pirate radio in the UK, the cryptic message that late-night DJ Bob gives to Carl to give to Carl's mother is: "Muddy Waters Rocks."

In 1990, the television show Doogie Howser, M.D. featured an episode called "Doogie Sings the Blues" with the main character, Blind Otis Lemon, based on Muddy Waters, with references to his influence on the Rolling Stones and Led Zeppelin, along with the performance of "Got My Mojo Working" by Blind Otis Lemon. He is also referred to as the original "Hoochie Coochie Man".

The Rock and Roll Hall of Fame listed four songs of Muddy Waters among the 500 Songs That Shaped Rock and Roll.

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Muddy Waters released approximately sixty singles (120 "sides") during his career, sixteen of which made the charts. These were issued on Chess Records, except for his 1941 recordings for the Library of Congress and his 1947 to early 1950 singles, which were issued on Aristocrat Records. The list shows the peak position the single reached on the Billboard R&B chart.

Muddy Waters also recorded several singles as a sideman with Jimmy Rogers, Little Walter, Junior Wells, Sonny Boy Williamson II, Otis Spann, and others.

Muddy Waters released about thirty albums during his career, including compilation albums. Since his death in 1983, numerous compilation and live albums have been released by a number of record companies (allmusic lists over 200 compilations). The following lists most of the albums released during his career and the more recent and available compilations released after his death.