In Home, her co-stars include her daughter, Eulala Scheel. One central scene called for her to bare her breasts, with the missing breast "removed" using computer-generated imagery. In 2008, she appeared in Home playing a woman who has had a mastectomy. Also in 2007 she shared top billing with Kevin Bacon in Rails & Ties, the directorial debut of Alison Eastwood. In 2007, Harden appeared in several films, including Sean Penn's critically acclaimed Into the Wild, and Frank Darabont's The Mist (opposite Thomas Jane and Laurie Holden), based on the novella by Stephen King. She reprised the role in the series' eighth season premiere and again in the twelfth season episode "Penetration" as a rape victim (aired November 10, 2010). In 2007, this role earned Harden her first Emmy Award nomination for best guest actress in a drama series. Harden guest-starred as FBI undercover agent Dana Lewis posing as a white-supremacist in "Raw", an episode of the popular crime drama Law & Order: Special Victims Unit. In 2003, she was again nominated in the same category for Mystic River. Harden was awarded the 2000 Academy Award for Best Supporting Actress for her portrayal of painter Lee Krasner in Pollock (2000).
The winner in that category was Debra Monk in Redwood Curtain. The role earned her critical acclaim and she received a Tony Award nomination (Best Featured Actress in a Play).
In 1993, Harden debuted on Broadway in the role of Harper Pitt (and others) in Tony Kushner's Angels in America.
Notable film roles include The Imagemaker (1986), her first screen role, in which she played a stage manager the Disney sci-fi comedy Flubber (1997), a popular hit in which she co-starred with Robin Williams the supernatural drama Meet Joe Black (1998) Labor of Love (1998), a Lifetime Television movie in which she starred with David Marshall Grant and Space Cowboys (2000), an all-star adventure-drama about aging astronauts. Throughout the 1990s, she continued to appear in films and television.
In 1992, she played actress Ava Gardner alongside Philip Casnoff as Frank Sinatra in the made for TV miniseries Sinatra. Even so, at the time, living in New York City, she had to go back to doing catering jobs "because I didn't have any money". She appeared in the Coen brothers' Miller's Crossing (1990), a 1930s mobster drama in which she first gained wide exposure. Throughout the 1980s, she appeared in several television programs, including Simon & Simon, Kojak, and CBS Summer Playhouse. Harden's first film role was in a 1979 student-produced movie at the University of Texas. She graduated from Surrattsville High School in Clinton, Maryland in 1976, the University of Texas at Austin with a BA in theatre, and the Graduate Acting Program at New York University's Tisch School of the Arts with a Master of Fine Arts. Harden's family frequently moved because of her father's job, living in Japan, Germany, Greece, California, and Maryland. One of Harden's brothers is named Thaddeus, as is her former husband. Harden, one of five children, was born in La Jolla, California, the daughter of Texas natives Beverly (née Bushfield), a housewife, and Thad Harold Harden, who was an officer in the United States Navy.