In 1973, Lithgow debuted on Broadway in David Storeys The Changing Room, for which he received both the Tony and Drama Desk Award as Best Featured Actor in a Play. The following year he starred opposite Lynn Redgrave in My Fat Friend, and in 1976 he starred opposite Meryl Streep in Arthur Millers A Memory of Two Mondays. He was nominated for the Best Actor Tony Awards for Requiem for a Heavyweight (1985) and M. Butterfly (1988).
Lithgow is probably most widely known for his starring role as Dick Solomon in the 1996–2001 NBC sitcom 3rd Rock from the Sun. He was nominated for a Primetime Emmy Award in the category Outstanding Lead Actor in a Comedy Series in each of the program's six seasons and won three times, in 1996, 1997, and 1999. His son Ian regularly appeared alongside him as Leon, one of his physics students. In 1986, Lithgow received a Primetime Emmy Award in the category Outstanding Guest Performer in a Drama Series for his appearance in the episode The Doll of the Amazing Stories anthology series. Additionally, Lithgow has been nominated for an Emmy Award for Outstanding Supporting Actor in a Limited Series or a Special for The Day After (1983), and two Emmy Awards for Outstanding Lead Actor in a Miniseries or a Special for Resting Place (1986) and My Brother's Keeper (1995).
In September 2009, Lithgow joined the cast of Dexter as Arthur Mitchell, a serial killer and Dexter Morgan's nemesis. He won a Golden Globe Award for this role, and won an Emmy for Outstanding Guest Actor In A Drama Series.