Although Spano has played mostly supporting parts in TV and films, he was often cast in classical leading roles on stage since his 1967 debut. While a member of the Berkeley Repertory Theatre, he played "Hamlet", Brick in "Cat on the Hot Tin Roof" and Oberon in "A Midsummer Night's Dream", among a host of other roles. When not on stage, he was a founding member of The Wing, an improvisational troupe. Although he broke into film work with a bit parts in "One Is a Lonely Number" (1972) and George Lucas' "American Graffiti" (1973) and into TV with a guest appearance on the ABC series "The Streets of San Francisco", Spano did not migrate to Southern California until the late 70s. He worked as an episodic guest performer until he was cast in the ensemble of "Hill Street Blues". When that acclaimed series left the air, Spano returned to episodic work, winning a 1989 Emmy for a performance as a death row inmate who proclaims his innocence yet invites a radio call-in show host (Gary Cole) to witness his execution on "Midnight Caller" (NBC). In the 80s and 90s, Spano also did TV longforms as well, including a key role in the miniseries "The Big One: The Great Los Angeles Earthquake" (NBC, 1990). Spano was back on series TV as nemesis to Patty Duke in the short-lived "Amazing Grace" (NBC, 1995).

Spano's feature film work has not been as extensive. He has had small roles in features including Alan Rudolph's "Roadie" (1980) and "The Incredible Shrinking Woman" (1981). In 1995, he was the NASA Director in Ron Howard's "Apollo 13". The following year, he was a police captain investigating the murder of an archbishop in "Primal Fear" for director Gregory Hoblit, with whom Spano worked on "Hill Street Blues".