Epstein's father, Sam, was a top local record producer who worked with various rock and roll and soul groups in the 1950s and 1960s.

[3] In the late 1960s and early 1970s, Howie played mostly rhythm guitar or mandolin and sang in a number of both rock and roll and country Milwaukee bands[1] that were regionally popular, including MHB Experience, Egz, Winks, Forearm Smash, and The Craze.

When he felt he had gone as far as he could go in Milwaukee, Epstein decided to move to New York City, but before he could pack his gear, he was lured to the West Coast by a drummer friend to play bass in a new band that singer-songwriter John Hiatt was forming in Los Angeles.

Consequently, when Ron Blair, who had been bassist with Tom Petty and The Heartbreakers since the band's inception in 1976, announced that he was quitting due to burnout, Epstein was recruited to replace him.

[4] In later interviews, Petty admitted that Epstein's behavior had become unpredictable: "He was just degenerating on us to the point where we thought keeping Howie in the band was actually doing him more harm than getting rid of him.

[1] Epstein played bass on recordings by Eric Andersen, Bob Dylan,[6] Carlene Carter, Johnny Cash, John Hiatt, Stevie Nicks, Roy Orbison, Carl Perkins, John Prine, Linda Ronstadt, Del Shannon, The Textones, The Village People and Warren Zevon.

Epstein produced two albums for John Prine, 1991's The Missing Years, which won a Grammy Award[6] for Best Contemporary Folk Recording, and Lost Dogs and Mixed Blessings.

[4] Epstein formed a creative and personal partnership with Carlene Carter, the daughter of country music stars June Carter Cash and Carl Smith and stepdaughter of country music star Johnny Cash, following her divorce from the English singer-songwriter Nick Lowe.

Epstein produced Carter's hit album I Fell in Love (1990) and co-authored the title track with his longtime collaborator, Milwaukee songwriter Perry M. Lamek.

[6] Epstein was taking antibiotics for an illness and had recently suffered from influenza, stomach problems, and an abscess on his leg, friends said.

[7] In response to Epstein's death, Petty wrote the following in an article for Rolling Stone: "...there's a great sadness, because Howie was never not a Heartbreaker.