Polito was born on December 29, 1950 in Philadelphia, Pennsylvania to John and Delaida “Dee” (née Pompei) Polito. He had an older brother and sister, Rosemary Simpson and Jack Polito, an animator. After acting at the West Philadelphia Catholic High School for Boys, he studied theater at Villanova University. Polito was openly gay. He married fellow actor Darryl Armbruster on October 16, 2015, fifteen years after they first met.

Polito won an Obie Award in 1980 for his theater performances off Broadway and for his lifetime of work in film and television he received the Maverick Spirit Event Award at Cinequest Film Festival in 2005. In 2012, he won the award for “Best Actor in a Short Film” at Hollywood Reel Independent Film Festival.

Polito was a regular in the Coen brothers movies appearing in five of their films. The Coens had seen Polito in the New York stage adaptation of Death of a Salesman in 1986 playing Howard Wagner. They approached him to play the part of The Dane in Miller’s Crossing (1990), but after reading the script he turned them down saying he would only play the Italian gangster Johnny Caspar. The Coens auditioned several other actors but eventually used Polito after they made him read his entire role cold.

He was offered the role of Lou Breeze in their next film Barton Fink (1991), in a role which was written especially for him. Again he turned down the Coens offer saying he wanted to play the part of movie producer Jack Lipnick. Actress Frances McDormand persuaded him to take the role saying it would change his career. He later appeared in The Hudsucker Proxy (1994) as an eccentric businessman, The Big Lebowski (1998) as a private detective and finally in 2001 as a flirtatious salesman in The Man Who Wasn’t There.

The show was rating poorly and the producers were under pressure from NBC to include a new female character (Megan Russert) in the hope of gaining broader appeal. As a result, they decided to write out Polito’s character at the end of Season 2. Fontana assured him that he would be brought back later in the season, but Polito was unhappy and criticized the producers publicly, an action he later regretted. The outburst caused a rift with Fontana and the Crosetti character was killed off early in Season 3, with the explanation that the detective had committed suicide. This further infuriated Polito, who again complained to the media, triggering a public slagging match between him and Fontana. Interviewed about the situation in 2005, Polito expressed regret for his handling of the matter. He noted that he and Fontana subsequently patched up their differences, and as a result the Crosetti character returned to make a farewell appearance as a spirit in Homicide: The Movie.

He died from multiple myeloma on September 1, 2016, at the City of Hope Hospital, where he was being treated. Polito was 65 years old.