Along with Patrick Stewart, Marina Sirtis, Jonathan Frakes, and John de Lancie, Shimerman is one of only a few actors to play the same character on four or more different Star Trek series.

In addition to Star Trek, Shimerman has had roles as Pascal on Beauty and the Beast and as Principal Snyder in 19 episodes of Buffy the Vampire Slayer.

He has also starred as Anteaus in Stargate SG-1 as one of the Nox, an evil wizard in Charmed, appeared as Stan the caddy in an episode of Seinfeld, and as Dr. Patemkin on Leverage.

Shimerman has appeared in the first seven episodes as Judge Brian Hooper in the third season of Boston Legal, joining fellow Star Trek actors William Shatner, René Auberjonois, and Ethan Phillips.

He had a small cameo in the episode "Posse Comitatus" of The West Wing as Richard the III and another in the film as an Old Man in the subway in What the Bleep Do We Know!?.

He then lent his voice talent to BioWare for their games Jade Empire (as Emperor Sun Hai, Abbot Song, and the Innkeeper) and Mass Effect (as the original Salarian Councilor and Fai Dan).

In 2008, he voiced the character of Wilmer in an audio dramatization of The Maltese Falcon, which also featured actors Michael Madsen, Sandra Oh, and Edward Herrmann.

He reprised his roles as Dr. Nefarious and Andrew Ryan and also voiced a Vox Populi enemy in the crossover fighting game PlayStation All-Stars Battle Royale.

Shimerman co-authored a Star Trek: Deep Space Nine novel, The 34th Rule, with David R. George III, published January 1, 1999.

[9] Shimerman thought aspects of both himself and his Star Trek: Deep Space Nine character, Quark, were in the novel's interpretation of John Dee.