In 1903, W.C. Handy was waiting for a train in Mississippi and heard a Blues musician. He later called the style "the weirdest music I ever heard." Despite his first impression, Handy was inspired to compose his own Blues songs, most notably "Memphis Blues" and his immensely popular "St. Louis Blues." Blues' infectious spirit is exemplified through many songs and legendary stories. For instance, upon hearing "Good Night Irene," the governor of Louisiana was so moved that he granted the song writer, convicted murderer Huddy "Leadbelly" Ledbetter, a full pardon. In the 1930s, guitarist, vocalist, songwriter higher level of recognition through his recordings for Columbia Records.

At about the same time, musicologist Alan Lomax traveled through the southern United States recording a huge amount of Blues music for the Smithsonian Institution. Lomax's work and the popularity of Johnson and other Blues artists, especially Bessy Smith (also recorded by Columbia), brought Blues to national popularity. At this time, Blues was still an acoustic form played by individual guitarists /vocalists (or sometimes piano and vocalist) and occasionally small ensembles utilizing guitar and percussion instruments such as washboard, spoons, and even the musician's own body ("'hambone") rather than the drum set. The Blues changed greatly in the 1940s. Prior to that decade, Blues had been an almost exclusively acoustic music.

But in the post war period, Chicago based Blues artists such as Muddy Waters, Howlin' Wolf, Elmore James and Willie Dixon, and the West Coast based T-Bone Walker, began playing "'electric" Blues featuring the electric guitar, amplified vocals, bass (still upright bass at the time), and the drum set. By this time, Blues had matured to its standard 12 bar form (4 bars of the I chord, 2 bars IV, 2 bars 1, 1 bar V, 1 bar IV, 2 bars 1, played in 4/4 swung time) in which the vocal melody and lyrics were organized in an A-A-B structure. A well known song that exemplifies these characteristics is "T-Bone Shuffle," by T-Bone Walker, which has been recorded by innumerable artists. (Of course, there are many Blues songs in nonstandard forms; to cite but one example from this general period, Floyd Dixon's famous ""Hey Bartender" is a 16-bar Blues [featuring 8 bars of the I chord at the beginning of the pattern]).

At about the same time, a fusion took place between Swing and Blues, resulting in Jump Blues, which included horns and never strayed from swung time. The most prominent exponents of this enormously popular style were Louis Jordan, Junior Parker, and T-Bone Walker. By the mid 1950s, Rock n' Roll (which is usually played with straight eighth notes, rather than swung) had begun to achieve mass popularity, and Blues artists such as Chuck Berry and Bo Diddley began to explore the straight feel (while keeping the 12-bar form). An example is Chuck Berry's famous "Johnny B. Goode" (which is also nonstandard in that the V chord at the 9th bar "hangs" rather than descends to the IV at the 10th bar).

In the 1960s, white musicians and bands (especially in England) such as John Mayall, Eric Clapton, Savoy Brown, The Rolling Stones, and (in the U.S.) Paul Butterfield began playing the Blues. Ironically, they had much greater success than the African American musicians who had pioneered the form. But they did bring Blues to a far wider audience than it had ever had, and some of the established African American Blues players benefited from this in the form of recording contracts and concert gigs. With the death of Jimi Hendrix in 1971 and the end of the late 1960s, early 1970s cultural upheaval despite the arrival of a few exciting new Blues performers such as Son Seals Blues lost much of its audience. And with the rise of Disco and Punk, it appeared all but dead by the end of the 1970s.