Johnston made her professional stage debut with New York's Atlantic Theater Company, which was founded by playwright David Mamet.
During her association with that company, she appeared in such productions as As You Like It and Stage Door, among many others.
She has performed with the Naked Angels Theater Company in The Stand-In and Hot Keys, and with New York Stage and Film in Kim's Sister, with David Strathairn and Jane Adams.
For her performance in The Lights at Lincoln Center Theater, Johnston was nominated for a Drama Desk Award as Best Supporting Actress.

The show brought her to the attention of a Carsey-Werner television executive.
After numerous auditions in 1996 for the TV series 3rd Rock from the Sun, she won the role of Sally Solomon.
She starred in the series from 1996 to 2001.
The role earned her two Emmy Awards for Outstanding Supporting Actress in a Comedy Series.

She made her feature film debut in The Debt, winner of Best Short at the 1993 Cannes Film Festival.
In 1995, she played Kate in the film Backfire!
She played Esmeralda, a sea hag in Thrill Ride, a family friendly film released in 2016.
 Other television credits include guest-starring roles on the series Chicago Hope, Hearts Afire, and The 5 Mrs. Buchanans.
She was also the narrator in Microscopic Milton on the Disney Channel.
Her significant roles in commercially successful movies included Austin Powers: The Spy Who Shagged Me in 1999, Ice Age, and Music and Lyrics in 2007.
In 1998, she was a spokesmodel for the Clairol company, as well as appearing on Bad Religion's No Substance album cover.

Johnston appeared in the sixth and final season of Sex and the City.
In the episode entitled "Splat!",
her character, Lexi Featherston, an aging party girl, accidentally falls out of a window and dies (after saying, "I'm so bored I could die."),
prompting Carrie Bradshaw (played by Sarah Jessica Parker) to re-examine her life.
In 2005, Johnston was featured in six episodes of NBC's ER.
She was cast as Patsy in a proposed American remake of the British TV show Absolutely Fabulous, but the series was never picked up by a network.
She appeared in a recurring role in the 2009 season of Ugly Betty and had a single-episode appearance as a dominatrix in the second season opener of Bored to Death.

She starred in the TV Land sitcom The Exes, which ran for four seasons between November 30, 2011, and September 16, 2015.
In 2018, she began a recurring role on the CBS sitcom Mom, and was upgraded to series regular for season 7 (2019–2020).
Johnston made her professional stage debut with New York's Atlantic Theater Company, which was founded by playwright David Mamet. During her association with that company, she appeared in such productions as As You Like It and Stage Door, among many others. She has performed with the Naked Angels Theater Company in The Stand-In and Hot Keys, and with New York Stage and Film in Kim's Sister, with David Strathairn and Jane Adams. For her performance in The Lights at Lincoln Center Theater, Johnston was nominated for a Drama Desk Award as Best Supporting Actress.
The show brought her to the attention of a Carsey-Werner television executive. After numerous auditions in 1996 for the TV series 3rd Rock from the Sun, she won the role of Sally Solomon. She starred in the series from 1996 to 2001. The role earned her two Emmy Awards for Outstanding Supporting Actress in a Comedy Series.
She made her feature film debut in The Debt, winner of Best Short at the 1993 Cannes Film Festival. In 1995, she played Kate in the film Backfire! She played Esmeralda, a sea hag in Thrill Ride, a family friendly film released in 2016.  Other television credits include guest-starring roles on the series Chicago Hope, Hearts Afire, and The 5 Mrs. Buchanans. She was also the narrator in Microscopic Milton on the Disney Channel. Her significant roles in commercially successful movies included Austin Powers: The Spy Who Shagged Me in 1999, Ice Age, and Music and Lyrics in 2007. In 1998, she was a spokesmodel for the Clairol company, as well as appearing on Bad Religion's No Substance album cover.
Johnston appeared in the sixth and final season of Sex and the City. In the episode entitled "Splat!", her character, Lexi Featherston, an aging party girl, accidentally falls out of a window and dies (after saying, "I'm so bored I could die."), prompting Carrie Bradshaw (played by Sarah Jessica Parker) to re-examine her life. In 2005, Johnston was featured in six episodes of NBC's ER. She was cast as Patsy in a proposed American remake of the British TV show Absolutely Fabulous, but the series was never picked up by a network. She appeared in a recurring role in the 2009 season of Ugly Betty and had a single-episode appearance as a dominatrix in the second season opener of Bored to Death.
She starred in the TV Land sitcom The Exes, which ran for four seasons between November 30, 2011, and September 16, 2015. In 2018, she began a recurring role on the CBS sitcom Mom, and was upgraded to series regular for season 7 (2019–2020).
Kristen Johnston