She played roles in the films Shag, Hiding Out, Mystic Pizza, SLC Punk!, The Last Supper and Double Jeopardy.

On television, she played Special Agent Monica Reyes on The X-Files, Elizabeth Bartlet Westin on The West Wing, Diane Gould on Halt and Catch Fire, Eileen Caffee on Brotherhood, Sarah Gunning on Midnight Mass, Charlotte Millwright on The Bridge and Sheriff Althea Jarry on the seventh and final season of Sons of Anarchy.

Gish portrayed Anne Hampton, the doomed second wife of Rhett Butler, in 1994 in the TV mini series Scarlett.

In 1997, she starred in the TV movie True Women as Euphemia Ashby alongside Dana Delany and Angelina Jolie.

In 2001, Gish joined the cast of The X-Files as Special Agent Monica Reyes after series star David Duchovny announced his intention to leave the show.

While it is generally agreed their performances were good,[citation needed] ratings continued to drop with the departure of Duchovny and his dynamic partnership with Anderson; the ninth season of The X-Files became the show's last until 2016.

In 2006, Gish played the role of Julia in the independent movie The Celestine Prophecy and co-starred in Candles on Bay Street alongside Eion Bailey and Alicia Silverstone.

The same year she landed a lead role in the Showtime drama Brotherhood as Eileen Caffee, and appeared in 29 of the 33 episodes in the series' three-season run.

[5] From 2013 to 2014, Gish was part of the main cast in the FX series The Bridge, in which she played Charlotte Millwright, a widow who discovers that her recently deceased husband had secrets on both sides of the US–Mexican border.

Two years later she had a recurring role as the caretaker Mrs. Dudley in the Netflix series The Haunting of Hill House, based loosely off of Shirley Jackson's novel of the same name.