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Musicians of the state's Delta region were historically significant to the development of the blues. Their laments arose out of the region's hard times after Reconstruction. Although by the end of the 19th century, two-thirds of the farm owners were black, continued low prices for cotton and national financial pressures resulted in most of them losing their land. More problems built up with the boll weevil infestation, when thousands of agricultural jobs were lost. Many Mississippi musicians migrated to Chicago and created new forms of jazz and other genres there.

Jimmie Rodgers, a native of Meridian and white guitarist/singer/songwriter known as the "Godfather of Country", also played a significant role in the development of the blues. He and Chester Arthur Burnett were friends and admirers of each other's music. Rodgers was supposed to have given Burnett his nickname of Howlin' Wolf. Their friendship and respect is an important example of Mississippi's musical legacy. While the state has had a reputation for being the most racist in America, individual musicians created an integrated music community. Mississippi musicians created new forms by combining and creating variations on musical traditions from Africa with the musical traditions of white Southerners, a tradition largely rooted in Scots–Irish music.

The state is creating a Mississippi Blues Trail, with dedicated markers explaining historic sites significant to the history of blues music, such as Clarksdale's Riverside Hotel, where Bessie Smith died after her auto accident on Highway 61. The Riverside Hotel is just one of many historical blues sites in Clarksdale. The Delta Blues Museum there is visited by tourists from all over the world. Close by are "Ground Zero" and "Madidi", a contemporary blues club and restaurant co-owned by actor Morgan Freeman.

Mississippi has also been fundamental to the development of American music as a whole. Elvis Presley, who created a sensation in the 1950s as a crossover artist and contributed to rock 'n' roll, was a native of Tupelo. From opera star Leontyne Price to the alternative rock band 3 Doors Down, to gulf and western singer Jimmy Buffett, to rappers David Banner and Afroman, Mississippi musicians have been significant in all genres. .