For playing a drug-addicted lesbian photographer in High Art (1998), Sheedy won the Independent Spirit Award for Best Female Lead.

She also starred in the films Twice in a Lifetime (1985), Short Circuit (1986), Betsy's Wedding (1990), Only the Lonely (1991), and Life During Wartime (2009), as well as the series Single Drunk Female (2022–2023).

Her mother, Charlotte (née Baum), is a writer and press agent who was involved in women's and civil rights movements,[2] and her father, John J. Sheedy Jr., is a Manhattan advertising executive.

She was the first cis-gender female to play the part of the genderqueer Hedwig, but her run ended early amid "mixed" reviews.

[16] She was reunited with Breakfast Club co-star Anthony Michael Hall when she became a special guest star on his television show The Dead Zone, in the second-season episode "Playing God", from 2003.

[17] Sheedy has also appeared in the 2007 episode "Leapin' Lizards" of C.S.I., in which she played a woman who murdered her boyfriend's wife while mixed up in a cult.

On March 3, 2008, Sheedy was introduced as the character Sarah in the ABC Family show Kyle XY.

She stated in Los Angeles Times that the relationship led her to abuse drugs, a claim Sambora denied.

[22] In 1985, Sheedy was admitted to Hazelden Foundation and in the 1990s was treated for a sleeping pill addiction,[6] an experience she drew on for her role as a drug-addicted photographer in High Art.