Picardo has shifted easily between comedy and drama since his days on the New York and California stage. As a pre-med at Yale College, he developed an interest in acting in his sophomore year. After landing a role in a campus production of Leonard Bernstein's "Mass", Picardo played a lead in the European production and caught the maestro's eye. When Bernstein urged him to study acting in NYC, the budding performer asked the great man to break the news to his mother. He did and Picardo changed majors from biology to drama in his junior year. He moved to New York after graduation and soon found roles on and off-Broadway in the likes of "Gemini" (with Danny Aiello) and "Tribute" (opposite Jack Lemmon). Picardo reprised the latter role in the 1979 Los Angeles production where he was seen by the young filmmaker Joe Dante. He also appeared in productions of "Geniuses" and "Beyond Therapy" and won a Drama-Logue Award for his performance in "The Normal Heart" at the Berkeley Repertory Theater.

Picardo entered films and TV in 1980, debuting in the former medium with Dante's breakthrough horror-comedy "The Howling". He went on to become part of the director's informal stock company, appearing in most of Dante's subsequent features and several of his TV projects. The collaboration includes playing two outrageously silly-looking aliens in "Explorers" (1985), a mean corporate ax in "Gremlins 2: The New Batch" (1990) and a put-upon theater manager in "Matinee" (1993). Picardo's other feature credits include Bob Fosse's "Star 80" (1983), as an interviewer, "Total Recall" (1990), as the disconcertingly accommodating voice of Arnold Schwarzenegger's murderous cab, and John Candy's swan song "Wagon's East!" (1994).