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Pierce was born David Pierce on April 3, 1959, in Saratoga Springs, New York. He is the youngest of four children. His father, James Joseph Pierce, was a salesman, and his mother, Laura Marie Hughes, was a homemaker. Pierce attended Saratoga Springs High School, where he was a member of the drama club. After graduating from high school, Pierce attended Yale School of Drama, where he received a Master of Fine Arts degree in 1984.

Pierce began his acting career in the theater. He appeared in a number of off-Broadway productions, including The Threepenny Opera, The Playboys, and A Midsummer Night's Dream. In 1989, he made his Broadway debut in the play The Heidi Chronicles.

Pierce's breakthrough role came in 1993, when he was cast as Dr. Niles Crane on the NBC sitcom Frasier. The show was a spin-off of the popular sitcom Cheers, and it starred Kelsey Grammer as Frasier Crane, a psychiatrist who moves to Seattle to join his brother Niles, also a psychiatrist, in practice. Pierce's portrayal of Niles Crane was both hilarious and nuanced, and he quickly became a fan favorite. For his work on the show, Pierce won four Primetime Emmy Awards for Outstanding Supporting Actor in a Comedy Series, making him the only performer to have won four consecutive Emmys in that category.

After Frasier ended its run in 2004, Pierce continued to work in television and film. He has starred in a number of television series, including The Good Wife, The Good Fight, and Veep. He has also appeared in a number of films, including Wet Hot American Summer, Down with Love, and A Bug's Life.

In addition to his acting work, Pierce is also a director and producer. He has directed episodes of the television series Frasier, The Good Wife, and Veep. He has also produced a number of television projects, including The Good Fight and The Undoing.

Pierce is married to Brian Hargrove, a film producer. They have been together since 2002 and were married in 2008.