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Grier came to prominence with her titular roles in the films Coffy (1973) and Foxy Brown (1974); her other major films during this period included The Big Doll House (1971), Women in Cages (1971), The Big Bird Cage (1972), Black Mama, White Mama (1973), Scream Blacula Scream (1973), The Arena (1974), Sheba, Baby (1975), Bucktown (1975), and Friday Foster (1975). She portrayed the title character in Quentin Tarantino's crime film Jackie Brown (1997), and also appeared in Escape from L.A. (1996), Jawbreaker (1999), Holy Smoke!, (1999), Bones (2001), Just Wright (2010), Larry Crowne (2011), and Poms (2019).

On television, Grier portrayed Eleanor Winthrop in the Showtime comedy-drama series Linc's (1998–2000), Kate "Kit" Porter on the Showtime drama series The L Word (2004–2009), and Constance Terry in the ABC sitcom Bless This Mess (2019–2020). She received praise for her work in the animated series Happily Ever After: Fairy Tales for Every Child (1999).