Assembled with all of the band members' participation, Once In A Lifetime offers plenty for longtime fans as well as those just discovering the band. The three CDs provide the most comprehensive overview of the band ever released, compiling all the hits as well as album cuts and rarities. In addition to songs like "Psycho Killer," "Take Me To The River," "Life During Wartime," "Once In A Lifetime," "Burning Down The House," "And She Was," and "Wild Wild Life," the set holds fan favorites like "Pulled Up," "Artists Only," "Heaven," "Houses In Motion," "Slippery People," and "Creatures Of Love."

The audio discs include five previously-unreleased tracks: alternate versions of "Uh-Oh, Love Comes To Town" (with steel drums throughout the song), "New Feeling," "Cities" (with additional lyrics), and "Drugs" (featuring Robert Fripp on guitar), and "In Asking Land," an outtake from the Naked sessions. The set also includes "A Clean Break (live)," previously available only on the 1982 double live LP The Name Of This Band Is Talking Heads, and never before available on CD. Very early cuts like "Sugar On My Tongue," "Love -> Building On Fire," and "I Wish You Wouldn't Say That," are also featured, as well as "Sax and Violins," which was originally released on the Until The End Of The World soundtrack.

Talking Heads always used a strong visual element to complement their music and created some groundbreaking music videos. Their multimedia orientation is reflected by the inclusion of a fourth disc, a DVD of Storytelling Giant (Expanded), which compiles all of the band's music videos on DVD for the first time. The disc offers three videos never before on DVD (and which were not part of the 1988 VHS release of Storytelling Giant)-"Blind," "(Nothing But) Flowers," and "Sax And Violins"-as well as previously unseen additional interstitials.