David Byrne is well known as the musician who co-founded the group Talking Heads (1976–88) in New York. On record and in concert, the band was acclaimed by critics and audiences alike; more importantly, however, they have proven to be extremely influential. Talking Heads took popular music in new directions, both in terms of sound and lyrics, and also introduced an innovative visual approach to the genre. In 2002 Talking Heads were inducted into the Rock and Roll Hall of Fame. In 2003, Talking Heads released a lovely boxed set which includes a DVD of all the band's videos. In 2005 a Brick was released with the complete studio catalog on dualdisc with previously unreleased audio and video material.

During his time with the group, Byrne was involved with several other projects:
• The Catherine Wheel, an evening-length ballet score for choreographer Twyla Tharp
• Music videos, director
• My Life in the Bush of Ghosts, a collaborative record with Brian Eno incorporating "found" voices such as radio preachers, talk show guests and Arabic singers (re-release with additional tracks in March 2006)
• the Knee Plays, a brass band-and-spoken word score for a theater piece, the Knee Plays, directed by Robert Wilson. A re-mastered CD with bonus tracks (with bonus DVD) was released in 2007.
• Stop Making Sense (1984), directed by Jonathan Demme, winner of Golden Globes, best documentary
• True Stories, 1986 feature film directed by Byrne
• The Last Emperor, 1987, DB collaborates on score for Bertolucci film, wins Oscar.
• Luaka Bop, Byrne's record label, was founded in 1988
• The Forest, 1989, an orchestral score with mostly wordless vocals for theater piece dir by Robert Wilson
• Ilé Aiyé: The House of Life, 1989, a documentary on African religion in Brazil