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Wiest is perhaps best known for her unforgettable appearances in five Woody Allen films: The Purple Rose of Cairo, September, Radio Days, Hannah and Her Sisters, for which she won the Academy Award for Best Supporting Actress, and Bullets over Broadway, for which she also won the Academy Award for Best Supporting Actress. She also received an Academy Award nomination for her performance in Ron Howard's Parenthood.

Currently, Wiest is also seen by television viewers as district attorney Nora Lewin in the acclaimed, Emmy Award-winning series Law and Order. Among Wiest's extensive credits are such films as I'm Dancing As Fast As I Can, Footloose, The Lost Boys, Edward Scissorhands, Little Man Tate, The Scout, Cookie, Cops and Robbersons, The Birdcage, The Associate, Practical Magic, The Horse Whisperer and Portofino. She also starred in Peter Cohn's Drunks which was screened at the 1996 Sundance Film Festival, where she was honored with the Piper-Heidsieck Tribute for Independent Vision.

Wiest, who began her career touring with the American Shakespeare Company, earned the Obie, Clarence Derwent and Theatre World Awards as Best Actress for her performance in the The Art of Dining. She made her stage-directing debut with Not About Heroes at the Williamstown Playhouse and starred in The Summer House at the Lincoln Center. On television, Wiest also starred in the Canadian series Road to Avonlea, for which she won an Emmy Award in 1997.