Wim Wenders looks at the dramatic tension in the blues between the sacred and the profane by exploring the music and lives of three of his favorite blues artists: Skip James, Blind Willie Johnson and J. B. Lenoir. Part history, part personal pilgrimage, the film tells the story of these lives in music through an extended fictional film sequence (recreations of '20s and '30s events - shot in silent-film, hand-crank style), rare archival footage, present-day documentary scenes and covers of their songs by contemporary musicians such as Shemekia Copeland, Alvin Youngblood Hart, Garland Jeffreys, Chris Thomas King, Cassandra Wilson, Nick Cave, Los Lobos, Eagle Eye Cherry, Vernon Reid, James "Blood" Ulmer, Lou Reed, Bonnie Raitt, Marc Ribot, The Jon Spencer Blues Explosion, Lucinda Williams and T-Bone Burnett.

J. B. Lenoir (1929 - 1967) was an American blues guitarist and singer-songwriter, active in the Chicago blues scene in the 1950s and 1960s. In 1965 the Swedish/American couple Rönnog and Steve Seaberg visited J.B. at his home on the South Side of Chicago and recorded 30 minutes of music and conversation. Parts of the film was used in "Soul of a Man" (2003).

This film by John Jeremy grew from photographs and field recordings made by Paul Oliver on a journey through the South in 1960. Oliver, a British architectural historian who devoted years to researching African American blues, memorialized the journey also in his 1963 book Conversation with the Blues. The film includes the voices and music of Blind James Brewer, James “Butch” Cage, Gus Cannon, Walter Davis, Blind Arvella Gray, Sam “Lightnin” Hopkins, James “Stump” Johnson, Lonnie Johnson, J. B. Lenoir, Charles Love, “Little Brother” Montgomery, James Oden, Edwin Buster Pickens, Sam Price, Robert Curtis Smith, Otis Span, Willie Thomas, Henry Townsend, Wade Walton, and others unidentified.