Pierce made his first brief screen appearance as a doomed trucker in James Cameron's "The Terminator" (1984). In 1988, billed under his full name, David Hyde Pierce, he had a bit part as a bartender in "Bright Lights, Big City" (1988). Additional small film roles followed in "Rocket Gibraltar", "Crossing Delancey" and "Vampire's Kiss" (all 1988). Pierce went on to larger, though still decidedly supporting, roles as Jeff Bridges' agent in Terry Gilliam's "The Fisher King" and Dianne Wiest's assistant in Jodie Foster's directorial debut "Little Man Tate" (both 1991). He was a member of Meg Ryan's family in Nora Ephron's "Sleepless in Seattle" and the obstetrician delivering Morticia's son in "Addams Family Values" (both 1993) as well as Jack Nicholson's underling in "Wolf" (1994). Oliver Stone cast the actor for his likeness to the real-life John Dean in the biopic "Nixon" (1995). Pierce had a rare romantic role as an astrophysicist who intrigues a camp counselor (Janeane Garofalo) in the period comedy "Wet Hot American Summer" (2001).

Television sitcoms have provided Pierce with two showcase roles. He played a terribly depressed, comically suicidal congressman on Norman Lear's fleeting political sitcom, "The Powers That Be" (NBC, 1992-93). Pierce followed with a major winner, the "Cheers" spin-off "Frasier" (NBC, 1993-2004). Originally, the series did not feature a sibling for Kelsey Grammer's title character, but producers were struck by Pierce's physical resemblance to Grammer and specifically created the role of Niles Crane, the snobbish, neurotic younger brother, for Pierce. Playing well off Grammer and co-stars John Mahoney, Peri Gilpin and Jane Leeves, Pierce created a memorable, deadpan scene-stealer, earning critical kudos and awards, including four Emmy Awards.

Keeping the laughs coming, Pierce was cast in the Steven Soderbergh-directed ensemble of "Full Frontal" (2002) in a seriocomic role as a magazine writer trapped in a complicated marriage, and used his voice for Farrelly Brothers' semi-animated "Osmosis Jones" (2001) and the Disney animated family feature "Treasure Planet" (2002). He was also seen in fine form as an uptight character reminsicent of the Tony Randall roles in the frothy Doris Day-Rock Hudson romantic comedies of the 1950s paid homage to in "Down With Love" (2003). The actor also provided, uncredited, the voice of supporting character Abe Sapien in the hit comic book adaptation "Hellboy" (2004).

Hyde's next high-profile project was on the stage, playing Sir Robin, a timid knight of the Round Table who soils himself whenever frightened, in Eric Idle's Broadway production of "Spamalot," a theatrical adaptation of the 1975 film "Monty Python and the Holy Grail." Looking lunatic in a long blond wig, Hyde Pierce earned rave reviews for his turn as the effete and dryly humorous Sir Robin, particularly with his humorous, showstopping number which declares "You won't succeed on Broadway if you don't have any Jews."

Away from the screen Hyde Pierce was a tireless advocate for Alzheimer's research, and appeared before the Senate in 2005 to announce the reintroduction of the Ronald Reagan Alzheimer's Breakthrough Act which would authorize Congress to double federal research funding annually.