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She began her career as a model and joined the cast of the soap opera General Hospital in 1981. After departing the show in 1983, she rose to prominence as a member of the Brat Pack, with roles in the films Blame It on Rio (1984), St. Elmo's Fire (1985), and About Last Night... (1986). She emerged a star with her portrayal of a grieving girlfriend in the romance film Ghost (1990), had further box office success in A Few Good Men (1992), Indecent Proposal (1993), and Disclosure (1994), and received a then-unprecedented $12.5 million to star in Striptease (1996). Her output decreased significantly after The Scarlet Letter (1995), The Juror (1996), and G.I. Jane (1997) fell below commercial expectations.

She has since held sporadic leading roles in arthouse films; supporting roles in Charlie's Angels: Full Throttle (2003), Bobby (2006), Mr. Brooks (2007), and Margin Call (2011); as well as television credits in If These Walls Could Talk (1996), Empire (2017–2018), and Feud: Capote vs. The Swans (2024). She received renewed recognition for her performance as an aging celebrity in the body horror film The Substance (2024), which earned her a Golden Globe and a nomination for the Academy Award for Best Actress.