Isaak's best known song is "Wicked Game". Though released on the 1989 album Heart Shaped World, an instrumental version of the song was later featured in the 1990 David Lynch 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. The song is on his 1995 Forever Blue album.
Isaak composed a theme song for U.S. 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.
In 2004, his track "Life Will Go On" was featured on Chasing Liberty's soundtrack, which starred Mandy Moore and Matthew Goode.