Catherine Keener was born in March of 1959 (some sources cite 1960) and raised in the Little Havana section of Miami, FL. The middle child of a large family, she attended Catholic schools and dreamed of becoming a nun until the realization that nuns were subservient to priests gave her second thoughts. She was a rambunctious teenager but maintained good enough grades to gain admission to Wheaton College in Massachusetts. The women’s college proved to be a revelation for the self-proclaimed “surfer chick” who, for the first time, was surrounded by strong, intellectual feminists. She studied literature, enrolled in her first theater course and expanded her interest in performing by taking a summer filmmaking course at New York University. After graduating in 1983, she moved to New York City, NY and began working for casting agent Gail Eisenstadt. When Eisenstadt was transferred to Los Angeles, Keener followed, only to have her boss give her an acting pep talk and her first small film role as a cocktail waitress in "About Last Night ..." (1986), where she exhorted Rob Lowe and Jim Belushi to "Go! Go! Go!" in their drinking contest, thus earning the newcomer a Screen Actors Guild card.

In a brief flirtation with television, Keener was cast as a young, cheeky sidekick on the short-lived cop show "Ohara" (ABC, 1987-88) before acting in 1989’s Outward Boundish feature "Survival Quest," which introduced her to future husband, actor Dermot Mulroney. She had small roles in Dennis Hopper's "Backtrack" (1990) and Blake Edwards' "Switch" (1991), before landing a timely entry into the fledgling indie film scene in Tom DiCillo's writing-directing debut "Johnny Suede" (1991), opposite then-unknown Brad Pitt's preening pop star, and earning her first critical recognition with a nomination as Best Female Lead at the Independent Spirit Awards. DiCillo took an instant liking to the actress, and feeling she had not gotten nearly enough screen time in “Johnny Suede,” he wrote a part for her in the short film "Scene Six, Take One" (1994), which he expanded into the feature "Living in Oblivion" the following year. An insider's look at low-budget filmmaking, the now legendary send-up featured James Le Gros as an egocentric star wreaking havoc on a shoestring shoot and Keener as an actress who – together with the inept director (Steve Buscemi), cinematographer (Dermot Mulroney) and crew – precipitates endless snags on an ill-fated indie production.

Following small roles in "The Destiny of Marty Fine" (1995) and Stacy Cochran's "Boys" (1996), Nicole Holofcener's "Walking and Talking" (1996) gave Keener a strong leading role as a continual loser in love coming to terms with the impending marriage of her best friend (Anne Heche). The “thinking woman’s chick flick” showcased Keener’s well-observed portrayal of an outspoken, contemporary woman plagued with complex doubts. For her role, she received another Best Lead Actress nomination from the Independent Spirit Awards. That same year, Keener enjoyed a wide audience with her portrayal of Demi Moore's judgmental sister-in-law in Nancy Savoca’s "1952" segment of HBO's popular series "If These Walls Could Talk." She reunited with DiCillo on "Box of Moonlight" (1996) where she gave a stand-out performance as a big personality stuck in a small town where she rocks the foundation of an uptight professional (John Turturro). DiCillo then cast Keener in "The Real Blonde" (1997), his comic exploration of the quest for integrity in the superficial worlds of fashion advertising, rock videos and soap operas.

Stephen Soderbergh helped boost Keener’s profile when he cast her in a memorable supporting role as a flamboyant, street smart magician’s assistant and ex-wife of a bank robber (George Clooney) in the gem "Out of Sight" (1998), adapted from the novel by Elmore Leonard. Back in the indie arena, Keener joined the ensemble cast of Neil LaBute's "Your Friends & Neighbors" (1998), a biting look at the tangled relationships of a group of bright, endlessly loquacious urbanites. She dipped her toe into mainstream Hollywood with a small role as Nicholas Cage's faithful wife in "8mm" (1999), but her career breakout came later that year with a starring role in Spike Jonze's "Being John Malkovich" (1999). The Charlie Kaufman script revolved around a file clerk (John Cusack) who discovers a portal into the mind of actor John Malkovich. Keener successfully went against type to play the no-nonsense boss who turns the journey into a paying attraction, while her domineering sex appeal has Malkovich, Cusack, and Cusack’s frumpy wife (Cameron Diaz) falling in love with her. The character-driven supporting actress was unaccustomed to a sexy leading role and it showcased spectacular new dimensions to the tune of Best Actress nominations at the Academy Awards, the Golden Globes and the Screen Actor’s Guild Awards.

Keener co-starred in the Sam Shepard adaptation "Simpatico" (1999) before kicking off the new millennium with director and friend Holofcener, who again tapped Keener for a smart and insightful portrait of very different sisters in 2001’s “Lovely and Amazing,” a starring role that earned the actress another Independent Spirit Award nomination. Keener was one of the high points in Steven Soderbergh's disappointing return-to-indie-style feature "Full Frontal" (2002) and worse for the actress was Danny DeVito's roundly dismissed dark comedy "Death to Smoochy" (2002), in which she played a TV executive caught in a war between two TV kiddie show hosts (Edward Norton and Robin Williams). One of several “career woman with tough exterior” roles, Keener next veered into typecasting territory when she took on a similar character in "S1m0ne" (2002), a mainstream release about a computer-generated actress which failed to excite audiences or critics. Keener followed up with rave reviews for writer-director Rebecca Miller's indie "The Ballad of Jack & Rose" (2005), where she played a mother who tries to integrate her family into the sheltered commune lifestyle of her boyfriend (Daniel Day-Lewis) and his daughter.

The year 2005 proved to be a pivotal time in Keener’s life. On the personal front, her 15-year marriage to Mulroney – long considered one of Hollywood’s most stable – came to an end following the couple’s separation in May. In the press, much was made of the fact that the Mulroney/Keener break-up came right on the heels of an even more shocking split – that of Keener’s close friend Brad Pitt and his wife, Jennifer Aniston. Being that the two couples often double-dated, the media could not help but speculate if there was something in the water. On a professional note, her onscreen work that year continued to test her range, while at the same time, place her in front of more mainstream film audiences than ever before. She had a supporting turn in the taut thriller "The Interpreter" (2005), where she was a welcome sight as the wisecracking partner of Sean Penn's federal agent. Keener’s flair for realistic, subtly played characters made her a brilliant casting choice to play opposite Steve Carell in the critically hailed summer comedy “40-Year-Old-Virgin.” Keener infused the “hot grandma” character with genuine warmth and a fun, sweet sexiness that led audiences to invest in the relationship between her and her inexperienced partner. Only a month later, Keener hit screens a fourth time in the pivotal role of Pulitzer Prize-winning author Nelle Harper Lee in “Capote” (2005). The film focused on author Truman Capote’s (Philip Seymour Hoffman) investigation of the grisly quadruple murder in Holcomb, KS that became the writer’s true crime classic, In Cold Blood. Lee had been an integral part of Capote’s research and her friendship an important aspect of the story. Keener’s outstanding portrayal was nominated for an Academy Award, SAG Award and a BAFTA for Best Supporting Actress.

Keener’s high-profile year did not spell the end of the actress’ dedication to independent film. She maintained her interest in smaller, creative films like “An American Crime” (2007), a chilling, fact-based tale where Keener played an abusive caretaker of a pair of siblings in 1960s Indiana. After the film’s premiere at Sundance in January, it was headed straight to DVD when Showtime picked it up for air later in the year. That twist of production fate enabled Keener to earn her first Emmy Award nomination for her leading role in the drama, as well as a Golden Globe nod. She returned to theaters in “Friends with Money” (2006), writer-director Nicole Holofcener’s ensemble comedy drama exploring the role of money in the lives of a group of women in their 40s. From Keener’s role as a successful television writer in the film, she made a 180-degree turn to play one half of a bohemian couple who take an idealistic young drifter under their wing in “Into the Wild” (2007). Sean Penn’s film based on the true story of Christopher McCandless topped dozens of critic’s top ten lists for the year, and led to a very busy 2008 for Keener, in which she co-starred in Charlie Kaufman’s reality-bending debut “Synecdoche New York,” the offbeat indie comedy about a high school drama teacher,“Hamlet 2,” and the Italian-set thriller “Genova.”