Gershon's film career has spanned over two decades. She made her film debut as a dancer in Beatlemania (1981) and her first speaking role in John Hughes' box-office hit, Pretty in Pink. Other film credits include Walter Hill's Red Heat opposite Arnold Schwarzenegger; Roger Donaldson's Cocktail opposite Tom Cruise; John Sayle's City of Hope, Robert Altman's The Player; Paul Verhoeven's Showgirls; the Wachowski Brother's Bound; John Woo's blockbuster Face/Off opposite John Travolta and Nicolas Cage; and Michael Mann's Oscar-nominated The Insider opposite Al Pacino. Gershon was last seen in Tom DiCillo's Delirious opposite Steve Buscemi, and Mars Callahan's What Love Is opposite Cuba Gooding Jr. and Anne Heche. Both films premiered at the 2007 Sundance Film Festival.

Gershon's notable television credits include the CBS mini-series, "Sinatra;" the TNT original movie "Legalese," opposite James Garner, Kathleen Turner and Mary Louise Parker; and David E. Kelley's action detective drama "Snoops." Gershon recently guest starred on ABC's Emmy Award-winning show "Ugly Betty" and has a recurring character on Larry David’s “Curb Your Enthusiasm” for HBO.

On stage, Gershon starred as Sally Bowles in Sam Mendes' Cabaret; in Camile opposite Kathleen Turner; and in Jon Robin Baitz's The Substance of Fire, both at the Long Warf Theatre; and in Eve Ensler's The Vagina Monologues. As a founding member of the New York-based theater company, Naked Angels, Gershon has appeared in numerous productions with the company.

Having always enjoyed singing and songwriting, Gershon's musical career blossomed with the independent film Prey for Rock & Roll. She received critical acclaim for her role as singer/guitarist Jacki. In addition to starring in and producing the film, Gershon produced and performed all of the songs in the film.  From this film stemmed the idea for Gershon's IFC documentary Rocked, which follows Gershon on the road touring with the rock band Girls Against Boys. Gershon has furthered her musical career with her latest CD In Search of Cleo. Gershon’s compilation of original songs creates a unique sound that mixes country, rock and jazz.

Most recently, Gershon co-authored a novel for young adults with her brother Dann entitled "Camp Creepy Time" (Putnam, 2007). The story centers on a 13 year old boy, Einstein P. Fleet, who is sent against his wishes to a summer camp which secretly serves as a kid smuggling operation. DreamWorks Films has already acquired the screen rights and will co-produce the film with Nickelodeon Films. Writer Richard LaGravenese is set to adapt the book for the screen.