- Trained at the Piven Theatre Workshop (founded by Jeremy Piven's parents) in Evanston, IL.
- Was a cast member of Saturday Night Live during the 1985 to 1986 season. (Developed her comedy chops as a fan of the work of Mel Brooks and Monty Python.)
- Nominated for Oscars in 1988 (Working Girl) and 1997 (In & Out).
- Voiced the part of Jessie the Cowgirl in Toy Story 2 (1999) and sang the Randy Newman ballad "When She Loved Me." (She again provided Jessie's voice in 2010's Toy Story 3.)
- Stipulated that her 2001 sitcom, What About Joan, be produced in Chicago so that she could be near her family.
- Has appeared in numerous films with brother John, including Sixteen Candles, High Fidelity, Say Anything... and War, Inc.
- A narrator for the children's series, Peep and the Big Wide World, an animated educational program.
- In 2010, appeared on Law & Order: Special Victims Unit as the adoptive mother of a runaway girl.
- 2012, Emmy — Outstanding Guest Actress in a Drama Series: Nominee
- 2014, Emmy — Outstanding Guest Actress in a Comedy Series: Nominee
- 2015, Emmy — Outstanding Guest Actress in a Comedy Series: Winner
- 1998, Golden Globe — Best Performance by an Actress in a Supporting Role in a Motion Picture: Nominee
- 1998, Critics' Choice Awards — Best Supporting Actress: Winner
- 1988, Oscar — Best Performance by an Actress in a Supporting Role: Nominee
- 1997, Oscar — Best Performance by an Actress in a Supporting Role: Nominee
- 2013, Emmy — Outstanding Guest Actress in a Drama Series: Nominee
- 2011, Emmy — Outstanding Guest Actress in a Drama Series: Nominee
- Dylan Burke — Son
- Nancy Cusack — Mother
- Susie Cusack — Sister
- Ann Cusack — Sister
- Richard Cusack — Father
- Bill Cusack — Brother
- Miles Burke — Son
- Richard Burke — Husband
- John Cusack — Brother
- University of Wisconsin, Madison, Wisconsin, United States (BA in English, 1985)
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