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Margolis went to Temple University briefly before moving to New York City, where he studied drama with Stella Adler and at the Actors Studio. He was perhaps most famous for his supporting roles in Scarface and the films of Darren Aronofsky: π, Requiem for a Dream, The Fountain, The Wrestler, and Black Swan. Aronofsky wrote the role of Father Avila in The Fountain specifically for Margolis.

He had recurring roles on numerous TV shows, including The Equalizer, HBO's Oz, Law And Order, Crossing Jordan and most recently Showtime's Californication and Breaking Bad. He also appeared in a first season episode of Quantum Leap.

In 1991, he also played Helmut Dieter in soap opera Santa Barbara.