She was Debbie Novotny in the Showtime cable television series Queer as Folk (2000–2005) and Madeline Westen on Burn Notice (2007–2013).

[4] Her maternal grandfather was Neil McCarthy,[5] a prominent Los Angeles attorney for Howard Hughes who had a large clientele of major film-studio executives and actors.

[citation needed] While she worked as a production assistant, Gless studied drama with acting coach Estelle Harman.

[11] At the beginning of her career, Gless appeared in numerous television series and TV movies, such as Revenge of the Stepford Wives, Faraday & Company with Dan Dailey and James Naughton in 1973 and 1974, Adam-12 season six, episode 24, Emergency!

That was in addition to a variety of guest-starring roles on television, including the part of the classy young secretary, Maggie Philbin, alongside Eddie Albert and Robert Wagner on the CBS private detective/con artist series Switch (1975–1978).

When the show was canceled after the third season, she thanked both Albert and Wagner for giving her career a jump start and remained close friends with them.

While under contract with Universal, she co-starred in a number of properties, including the 1979 Steven Bochco television sitcom, Turnabout (based on the Thorne Smith 1931 novel about a husband and wife who temporarily switch bodies), which failed to be a ratings blockbuster, and briefly in the sitcom House Calls (in which she replaced Lynn Redgrave, who had left due to a contract dispute).

Rosenzweig created the 1990–1992 CBS drama series The Trials of Rosie O'Neill for Gless, and uncredited she played a psychiatrist, who was only partially seen.

[12] In addition, Gless was a guest star on several episodes of the FX Network cable television series Nip/Tuck as an unstable agent, Colleen Rose, a role that netted her an Emmy Award nomination.

The film is based on a screenplay by the Jeff Award-winning playwright Claudia Allen and directed by Wendy Jo Carlton.

Gless had two appearances in London's West End, first in 1993 with Bill Paterson, when she created the role of Annie Wilkes in the stage version of Stephen King's Misery at the Criterion Theatre, and then in 1996, where she appeared opposite Tom Conti in Neil Simon's Chapter Two, at the Gielgud Theatre.

A production took place in London, transferring in November 2011 from Riverside Studios to the Aldwych Theatre, where the run closed on January 14, 2012.