After a year, he left the show to launch a movie career. His films include Caddyshack (1980), National Lampoon's Vacation (1983), and Fletch (1985).
The actor of Lebanese origin is best known for his role as manic-obsessive sleuth Adrian Monk on the TV series Monk. By 1991, one of his first television roles was as the Italian cabdriver Antonio Scarpacci in the sitcom Wings.
Shalhoub was pleasantly surprised to land the role after having a recurring role in the second season. Shalhoub affected an Italian accent for the role. In the same time period, Shalhoub played physicist Dr. Chester Ray Banton in the X-Files second-season episode "Soft Light." He later returned to series television in 1999, this time in a lead role on Stark Raving Mad opposite Neil Patrick Harris. The show did not attract much of an audience, and NBC cancelled the series in July 2000.
Shalhoub was nominated for Emmy Award for Outstanding Lead Actor in a Comedy Series seven times consecutively, from 2003-2009, and won in 2003, 2005, and 2006.