With a career spanning four decades, Isaak has released 13 studio albums, toured extensively with his band Silvertone, and received numerous award nominations.

As an actor, he played supporting roles and bit parts in films such as Married to the Mob, The Silence of the Lambs, Little Buddha, That Thing You Do!

[8] After graduating from college, Isaak put together his first band, Silvertone, a rockabilly group with James Calvin Wilsey (guitar), Jamie Ayres (bass), and John Silvers (drums).

[8] In 1985, Isaak signed a contract with Warner Bros. Records and released his first album, Silvertone,[3] to critical acclaim, including from John Fogerty.

Three tracks from the album -- "You Owe Me Some Kind of Love", "Blue Hotel", and "Lie to Me" –- were used in Episode 5 of the 1987 TV series "Private Eye".

That same year, "Suspicion of Love" by Isaak appeared in Married to the Mob, a hit movie starring Matthew Modine, Michelle Pfeiffer, and Dean Stockwell.

Chesnut spread the word to other radio stations and the single became a national top 10 hit in February 1991, peaking at number 6.

[13] The music video for the song was directed by Herb Ritts and was an MTV and VH1 hit; shot in black and white, it featured Isaak and supermodel Helena Christensen in a sensual encounter on the beach, caressing each other and whispering in each other's ears.

Another less-seen version of "Wicked Game" is directed by David Lynch and comprises scenes from the film Wild at Heart.

"Two Hearts" from Isaak's fourth album, San Francisco Days, was featured in the closing credits of True Romance, a 1993 film directed by Tony Scott, written by Quentin Tarantino, and starring Christian Slater and Patricia Arquette.

That year he released Forever Blue, Isaak's fifth album, and the accompanying tour featured Hershel Yatovitz on guitar.

Isaak performed at the 2015 AFL Grand Final, along with English singer Ellie Goulding and Canadian musician Bryan Adams.

A few of his larger film roles included David Lynch's Twin Peaks: Fire Walk with Me in 1992 and in the 1993 Bernardo Bertolucci-directed Little Buddha, in which he starred alongside Bridget Fonda and Keanu Reeves.

[citation needed] Isaak guest-starred in the special Super Bowl XXX edition of the television sitcom Friends ("The One After the Superbowl, Part One") in 1996,[18] and in 1998 he co-starred in the HBO miniseries From the Earth to the Moon as astronaut Ed White, who was the first American astronaut to do a spacewalk and who died in the 1967 Apollo 1 fire.

This adult sitcom featured Isaak and his band playing themselves, and the episode plots were based on fictional accounts of the backstage world of Isaak—the rock star next door.

The guests on the remaining seven episodes of the series were: Stevie Nicks, Glen Campbell, Michael Bublé, Chicago, The Smashing Pumpkins, Yusuf Islam, and Jewel.

[20] In April 2010, Isaak was the special guest during Conan O'Brien's The Legally Prohibited from Being Funny on Television Tour performance at the Nob Hill Masonic Center in San Francisco, California.

[22] In 2014, Isaak voiced the character of Enoch, the apparent ruler of the town of Pottsfield, in the second episode of the animated television miniseries Over the Garden Wall.