She received nominations for the Academy Award for Best Supporting Actress for her roles in the comedy-drama Working Girl (1988) and the romantic comedy In & Out (1997).

She has also provided the voice of Jessie in the Toy Story franchise (1999–present), for which she won an Annie Award, and Abby Mallard in Chicken Little (2005).

She starred on the Showtime hit drama/comedy series Shameless (2011–2021) as Sheila Jackson, a role for which she received five consecutive Primetime Emmy Award nominations, winning for the first time in 2015.

[3] Her mother, Ann Paula "Nancy" Cusack (née Carolan; 1929–2022),[4] was a former mathematics teacher and political activist.

[10] She has appeared with her brother John in 10 movies: Class (1983), Sixteen Candles (1984), Grandview, U.S.A. (1984), Broadcast News (1987), Say Anything... (1989), Grosse Pointe Blank (1997), Cradle Will Rock (1999), High Fidelity (2000), Martian Child (2007), and War, Inc. (2008).

In the film Addams Family Values (1993), she played psychotic serial killer Debbie Jellinsky, who marries and kills rich men.

[citation needed] Cusack narrates the public-TV animated series Peep and the Big Wide World.

[13] Cusack has received critical acclaim for her performance, receiving Primetime Emmy Award for Outstanding Guest Actress in a Drama Series nominations in 2011, 2012, and 2013, as well as a nomination for the Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series in 2014 and 2015, winning in the later year.