Kane appeared on the television series Taxi in the early 1980s, as Simka Gravas, the wife of Latka, the character played by Andy Kaufman, winning two Emmy Awards for her work.

[3][4] Due to her father's occupation, Kane moved frequently as a child; she briefly lived in Paris at age eight, where she began learning to speak French.

[10] Kane made her professional theater debut in a 1966 production of The Prime of Miss Jean Brodie starring Tammy Grimes, her first job as a member of Actors' Equity.

[11][12] Kane's on-screen career began while she was still a teenager, when she appeared in minor roles in films such as Desperate Characters and Mike Nichols's Carnal Knowledge in 1971, the latter of which led her to befriend lead actor Jack Nicholson.

[13] In 1975, Kane was cast in Joan Micklin Silver's feature-length debut Hester Street, in which she played a Russian-Jewish immigrant who struggles with her husband to assimilate in late 19th-century New York.

[5] Additionally, 1975 saw her appear as a bank teller in Sidney Lumet's crime drama Dog Day Afternoon, which received numerous Academy Award nominations in other categories that same year.

Despite this recognition, however, Kane has recounted waiting for approximately a year before being cast in her next role, which she has attributed to the trend of actors being typecast after receiving awards attention.

She has theorized that she was cast in Taxi in part due to her work in Hester Street, where a significant portion of her dialogue was spoken in Yiddish, since Simka speaks a fictional language with a vaguely Eastern European accent.

In 1987, Kane appeared in Ishtar, Elaine May's notorious box-office flop turned cult classic, playing the frustrated girlfriend of Dustin Hoffman's character.

That year also saw her make one of her most recognizable film appearances in Rob Reiner's fantasy romance The Princess Bride, where she played Valerie, the wife of Miracle Max (Billy Crystal).

In 1988, Kane appeared in the Cinemax Comedy Experiment Rap Master Ronnie: A Report Card alongside Jon Cryer and the Smothers Brothers.

During the same year, she was also featured in the Bill Murray vehicle Scrooged, where she portrayed a contemporary version of the Ghost of Christmas Present, depicted in the film as a fairy.

[30] She made her West End debut in January 2011 in a major revival of Lillian Hellman's drama The Children's Hour at London's Comedy Theatre, where she starred alongside Keira Knightley, Elisabeth Moss and Ellen Burstyn.

[34] Kane joined the cast due in part to her admiration of showrunner Tina Fey, with whom she had previously wanted to collaborate on the NBC series 30 Rock.

[38] That same year, she was featured in the recurring role of Bianca Nova in season one of the HBO series Los Espookys, where she reunited with her Unbreakable Kimmy Schmidt castmate Fred Armisen.

[43] In 2024, Kane starred in Nathan Silver's comedy film Between the Temples, in which she portrays a woman who, having been raised by secular parents, decides to have a bat mitzvah later in life.

[45] In December 2024, she was announced as part of the cast of Darren Aronofsky's upcoming film Caught Stealing, where she is slated to play a minor role in which she only speaks Yiddish.