made his film debut in Bright Lights, Big City, then appeared in the films Rocket Gibralter, Crossing Delancey, Terry Gilliam's The Fisher King, Jodie Foster's Little Man Tate, Sleepless In Seattle, Addams Family Values, Wolf, and Oliver Stone's Nixon, as John Dean. He currently provides the voice of "Slim, the Walking Stick" in Disney/Pixar Animation's A Bug's Life. His next film is Andrew Bergman's Jacqueline Susann biography, Isn't She Great, opposite Bette Midler, Nathan Lane, and John Cleese.

He is best known to TV audiences as Niles Crane, brother of Kelsey Grammer's title character, on the phenomenally successful Frasier, for which he has won multiple Emmy Awards. Additionally, Pierce won the American Comedy Award for Funniest Supporting Male Performer in a TV Series, a Screen Actors Guild Award for Best Supporting Actor, the Television Critics Association Award, and a Viewers For Quality Television Award for his brilliant portrayal of the character which wasn't intended to be part of the show until the producers, who were struck by the strong physical resemblance to Grammer, created the role for him.

After training for a career as a concert pianist and an education at Yale University, he began a distinguished acting career on the stage where he made outstanding appearances in Christopher Durang's Beyond Therapy and Wendy Wasserstein's The Heidi Chronicles on Broadway, and as Laertes opposite Kevin Kline as Hamlet at the New York Shakespeare Festival.