Thomas Wright "Fats" Waller was born May 21, 1904, in New York City, the seventh of eleven children (five of whom survived childhood) of Edward Martin Waller, a Baptist lay preacher and teamster, and Adeline Lockett Waller, a musician who gave him his first exposure to piano and organ. He began piano at six, later added reed organ, double bass, and violin, and worked in a grocery store to pay for lessons. Hearing pianist Ignacy Jan Paderewski at Carnegie Hall as a boy left a lasting impression. At sixteen he became house organist at Harlem's Lincoln Theatre, earning $23 a week accompanying silent films and vaudeville acts, and around the same time he met stride pianist James P. Johnson, who took him under his wing, taught him the demanding stride left-hand style, and introduced him to Harlem's rent-party and nightclub circuit.

Waller began recording in 1922 through Clarence Williams at Okeh Records, cutting sides behind blues singer Sara Martin, and the following year started making piano rolls for QRS while also meeting lyricists Andy Razaf and J.C. Johnson, both of whom became career-long collaborators. In 1926, talent scout Ralph Peer signed him to the Victor Talking Machine Company, and on November 17 of that year Waller cut his first solo sides, "St. Louis Blues" and "Lenox Avenue Blues." He composed prolifically for Harlem revues through the late 1920s; "Keep Shufflin'" opened in 1928 and moved to Broadway, and in 1929 two Razaf collaborations, "Honeysuckle Rose" (written for the revue "Load of Coal") and "Ain't Misbehavin'" (written for "Connie's Hot Chocolates"), became instant standards. When "Hot Chocolates" transferred to Broadway's Hudson Theatre in June 1929 with Louis Armstrong leading the pit orchestra, Armstrong's trumpet reading of "Ain't Misbehavin'" was received so well that he was brought up out of the pit to perform it onstage, helping turn the song into a national hit. That same year Waller cut a landmark run of unaccompanied piano sides for Victor, including "Handful of Keys," "Numb Fumblin'," "Smashing Thirds," and "Valentine Stomp," and led one of the first racially integrated recording dates, billed as Fats Waller's Buddies, with white and Black musicians together in the studio.

Waller built a parallel career on the radio through the early 1930s, first on CBS starting in 1930 and then on a two-year contract fronting "Fats Waller's Rhythm Club" on WLW in Cincinnati, developing the mix of virtuoso playing, comic patter, and mugging asides that became his trademark. In May 1934 he formed the small working band Fats Waller and His Rhythm, typically a sextet built around clarinetist/tenor saxophonist Gene Sedric, trumpeter Herman Autrey, guitarist Al Casey, bassist Cedric Wallace, and drummer Slick Jones, and began a prolific run of RCA Victor sides that made him a crossover star well beyond Black record buyers, among them "I'm Gonna Sit Right Down and Write Myself a Letter" and the manager-encouraged novelty numbers he turned into comic showcases. Hollywood took notice, casting him in the films "Hooray for Love" and "King of Burlesque" (both 1935).

New manager Ed Kirkeby took Waller to Britain and Scandinavia in 1938 and again in 1939, where he found more discerning audiences than at home, recorded for HMV, and composed the impressionistic solo-organ suite "London Suite." In 1938 Waller and his wife also became one of the first Black families to buy a home in Addisleigh Park, St. Albans, Queens, helping break a racial covenant later crossed by Count Basie, Lena Horne, and Ella Fitzgerald. He attempted to be taken seriously as a concert composer with a January 1942 Carnegie Hall performance that drew mixed reviews, wrote the score for the Broadway show "Early to Bed" (which opened in June 1943, making him the first Black composer to write a full score for a white Broadway cast), and appeared in the all-Black-cast film "Stormy Weather" (1943), reprising "Ain't Misbehavin'" opposite Lena Horne and Bill "Bojangles" Robinson.

By the early 1940s heavy drinking, which had begun in his teens, had worsened, and a wartime musicians' union recording ban further slowed his output. In October 1943 he contracted influenza while playing Hollywood's Zanzibar Room and ignored a doctor's advice to be hospitalized. Returning to New York by train, he died of bronchial pneumonia in the early hours of December 15, 1943, as the Santa Fe Chief stopped at Kansas City, Missouri; he was 39. His funeral drew more than 4,000 mourners to Harlem's Abyssinian Baptist Church, where Congressman Adam Clayton Powell Jr. eulogized him, and his ashes were later scattered over Harlem from an airplane.

Waller took the stride piano style he learned directly from James P. Johnson and pushed it further, driving tirelessly swinging, seamless octave-and-tenth left-hand patterns under a right hand full of rich three-note chord voicings and chromatic passing tones that anticipated and directly shaped Art Tatum's harmonic vocabulary. He was also jazz's first major organist, adapting stride technique to the pipe organ he affectionately called the "God box" and later to the Hammond, influencing swing-era organists including Milt Herth and Glenn Hardman, and by his own account giving a young Count Basie informal organ lessons in Boston. As a songwriter with Andy Razaf he produced a run of standards, "Ain't Misbehavin'," "Honeysuckle Rose," "Keepin' Out of Mischief Now," and "The Joint Is Jumpin'" among them, whose durability in the jazz and popular songbook far outlasted the era that produced them. His public persona, built on comic patter, mugging, and knowing asides delivered over otherwise serious musicianship, sometimes obscured his standing as a pianist and composer during his lifetime, but Dizzy Gillespie called him "my main man," and stride specialists Ralph Sutton and Don Ewell built their own careers directly on his model, adopting techniques like his "backward tenths." He composed hundreds of songs, though he sold outright rights to many of them for quick cash and lost composer credit on a number that were later assigned to other names.