Chris Isaak was born in Stockton, California, the son of Dorothy and Joe Isaak. Chris signed a contract to Warner Bros. Records in 1984 for his first album Silvertone. The tracks "Gone Ridin'" and "Livin' for Your Lover" from his album were featured in David Lynch's cult classic Blue Velvet. Isaak's contract was renewed in 1988 when Warner Bros. moved him to their Reprise Records label. His best-known song is "Wicked Game". Though released on the 1989 album HeartShaped World, an instrumental version of the song was later featured in the 1990 David Lynch film Wild at Heart Lee Chesnut, an Atlanta radio station music director who was obsessed with Lynch films, began playing the vocal version and it quickly became the station's most-requested song. Chesnut spread the word to other radio stations around the country and the single became a national top 10 hit in February of 1991. The music video for the song was directed by Herb Ritts and was a big MTV and VH1 hit; shot in black and white, it starred Isaak and Danish supermodel Helena Christensenrolling on the beach, embracing and whispering in each other's ears. Another less-seen version of the "Wicked Game" is directed by David Lynch and comprises scenes from the film Wild at Heart

In 1999, Isaak's "Baby Did a Bad, Bad Thing" was featured in Stanley Kubrick's final film, Eyes Wide Shut, starring Tom Cruise and Nicole Kidman The song is on his 1995 album Forever Blue. The music video for the song is directed by Herb Ritts, it was shot in color and it starred Isaak and French supermodel Laetitia Castain a motel room. This was Isaak's second collaboration with Ritts.

Isaak also composed a theme song for US late-night television variety/talk show, The Late Late Show with Craig Kilborn. In 2001, Isaak starred in his own television show, The Chris Isaak Show. It aired from March 2001 to March 2004 in the United States on the cable television network Showtime. This adult comedy show featured Chris Isaak and his band playing themselves with the episode plots based on fictional accounts of the backstage world of Chris Isaak--the rock star next door. In 2004, his track "Life Will Go On" was featured on Chasing Liberty's soundtrack, which starred Mandy Mooreand Matthew Goode His track "Two Heart" was featured in the closing credits of the 1993 film True Romance, directed by Tony Scott.

Isaak has also appeared in numerous films, mostly playing minor cameo roles, though he starred with Keanu Reeves and Bridget Fonda in the 1993 Bernardo Bertolucci-directed Little Buddha, and also played a major role in David Lynch's Twin Peaks: Fire Walk with Me (1992). Other motion pictures include Married to the Mob (1988), The Silence of the Lambs (1991), That Thing You Do! (1996) and A Dirty Shame (2004). Isaak was ranked #68 on VH1's 100 Sexiest Artists.