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Pfeiffer began her acting career with minor television and film appearances and secured her first lead role in Grease 2 (1982). Her breakthrough role as Elvira Hancock in Scarface (1983) propelled her into mainstream success, which continued with performances in The Witches of Eastwick (1987) and Tequila Sunrise (1988). Pfeiffer received her first of six consecutive Golden Globe Award nominations for Married to the Mob (1988). Her roles in Dangerous Liaisons (1988) and The Fabulous Baker Boys (1989) garnered her two consecutive Academy Award nominations, for Best Supporting Actress and Best Actress, respectively, and she won a Golden Globe Award for the latter.

Cemented as one of the highest-paid actresses of the 1990s, Pfeiffer starred in The Russia House (1990) and Frankie and Johnny (1991). In 1992, she played Catwoman in Batman Returns and received her third Academy Award nomination for Love Field, which she followed up with performances in The Age of Innocence (1993) and Wolf (1994). She also produced several of her own features through her company, Via Rosa Productions, including Dangerous Minds (1995). Reducing her workload to prioritise her family, Pfeiffer acted sporadically throughout the 2000s, starring in What Lies Beneath (2000), White Oleander (2002), Hairspray, and Stardust (both 2007).

Following another hiatus, Pfeiffer returned to prominence in 2017 with performances in Where Is Kyra?, Mother!, and Murder on the Orient Express, and received her first Primetime Emmy Award nomination for playing Ruth Madoff in The Wizard of Lies. In 2020, she received her eighth Golden Globe Award nomination for French Exit. Pfeiffer has played Janet van Dyne in the Marvel Cinematic Universe since 2018, beginning with Ant-Man and the Wasp.