Gilpin appeared on the TV series Cheers, playing Holly Matheson in the 21st episode of the 11th season, which aired in April 1993.

Along with the principal cast, Gilpin won a Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Comedy Series in 1999.

[citation needed] Gilpin and Frasier co-star Jane Leeves ran a production company, Bristol Cities (named from the cockney rhyming slang), whose projects included a Fox network pilot titled Minister of Divine, an American remake of the British sitcom The Vicar of Dibley with Kirstie Alley (another Cheers regular) in a starring role.

She has a supporting role on the television series Make It or Break It and has appeared on Law & Order: Criminal Intent.

[5] Gilpin has led efforts supporting cancer research awareness since the time her mother was diagnosed with the disease.