Keener's first film appearance was one line in About Last Night (1986). Although she struggled professionally over the next few years one low-quality project had an unexpected dividend. Keener met her future husband, actor Dermot Mulroney in 1987 while working on Survival Quest (1989), after Mulroney became stuck while attempting to scale a cliff.
She also guest-starred as an artist on an episode of Seinfeld called "The Letter". She played Jerry's girlfriend, an artist who painted the infamous portrait of Kramer. Keener then earned her first starring role in Johnny Suede with the then unknown Brad Pitt. Her performance gained critical acclaim and earned her her first Independent Spirit Award nomination for Best Female Lead. She went on to work with director Tom Dicillo, again, in Living in Oblivion (1995). Two years later she was once again nominated for an Independent Spirit Award for her performance in Walking and Talking, an independent cult-comedy film directed by Nicole Holofcener. Critics fell in love with Keener's naturalness onscreen.
In 2000, Keener earned her first Oscar nomination for Best Supporting Actress for her role in Being John Malkovich, directed by Spike Jonze. In 2001, she worked with director Nicole Holofcener in Lovely and Amazing garnering her a third Independent Spirit Award nomination. In 2002, she co-starred with Edward Norton in the off-Broadway revival of Burn This and the films Full Frontal, and S1m0ne, both of which were box office disappointments when released.
In 2005, she made a huge comeback starring in the political thriller The Interpreter, The Ballad of Jack and Rose, opposite Daniel Day-Lewis, and was cast as the love interest of Steve Carell in Judd Apatow's The 40-Year-Old Virgin. Keener's performance as writer Harper Lee in Capote (also 2005) earned her several awards and nominations, including her second Oscar nomination for Best Supporting Actress. In 2006, she starred in the film Friends with Money, directed by Nicole Holofcener.
In 2007, Keener played Jan Burres in Sean Penn's critically acclaimed film Into the Wild, based on Jon Krakauer's best-selling book of the same name. In 2008, her film An American Crime, the true story of Gertrude Baniszewski, a middle-aged mother who tortured and killed Sylvia Likens in her Indiana home, was aired on Showtime. Keener plays Baniszewski and her portrayal earned her an Emmy nomination in the Best Actress in a TV Mini-Series or Movie category. In 2008, Keener portrayed Philip Seymour Hoffman's wife Adele in the critically acclaimed Charlie Kaufman directorial debut, Synecdoche, New York. Keener played the title character's mother in the 2010 film Percy Jackson & the Olympians: The Lightning Thief, based on the series of books by Rick Riordan.
