Since her stepfather produced Woody Allen’s films, Holofcener spent enough time on Allen’s sets to be an extra in Take the Money and Run and Sleeper. Joffe was responsible for Holofcener’s first “real” job in the movie industry: a production assistant on Woody Allen’s A Midsummer Night’s Sex Comedy in 1982. She moved up to apprentice editor for Hannah and Her Sisters (1986).

Holofcener made her feature film writing and directing debut in 1996 with Walking and Talking, which starred Catherine Keener, Anne Heche, Todd Field, Liev Schreiber, and Kevin Corrigan. The film was critically acclaimed. Her understanding of modern, professional women made her an ideal choice to direct female-centric television shows like Sex and the City, Leap of Faith and Gilmore Girls. Holofcener also worked on an episode of the U.S. adaptation of Cold Feet.

She followed in 2001 with her second feature, Lovely and Amazing. Featuring performances by Catherine Keener, Brenda Blethyn, Emily Mortimer and newcomer Raven Goodwin, the film was not only critically acclaimed but did well at the box office.

After directing two episodes of the series Six Feet Under, Holofcener began work on her third film, Friends with Money, which featured Jennifer Aniston, Joan Cusack, Frances McDormand, and Catherine Keener. The film opened the 2006 Sundance Film Festival, and its screenplay was nominated for the 2006 Independent Spirit Award, while McDormand won the award for Best Supporting Female. The film received a limited release on April 7, 2006.

After viewing one of her college works, her stepfather wondered aloud if she shouldn’t make a career change. Disappointed, she became a clerk at a video store for a while, then entered Columbia’s graduate school program. At the time of his death in 2008, Charles Joffe had become one of the most ardent fans of his stepdaughter’s work. Angry received critical praise at Sundance. Holofcener has been viewed as an indie filmmaker despite the financial and critical success of her feature-length films. Many of the conventions of independent film are found in her movies. Many of Holofcener’s films are shot on location during their production.

Holofcener’s fourth feature, Please Give, premiered at Sundance and was screened at the Berlin International Film Festival and the Tribeca Film Festival. The film also won Holofcener the Robert Altman Award. The film also gained Holofcener a nomination with the Writers Guild of America Awards for Best Original Screenplay. It stars Keener in the duo’s fourth collaboration and was released in 2010. The film also features Oliver Platt, Rebecca Hall, Amanda Peet, and Sarah Steele.

Holofcener followed this up with Enough Said starring Julia Louis-Dreyfus, James Gandolfini, and Catherine Keener. The film premiered at the 2013 Toronto International Film Festival. The romantic comedy follows the character Eva, a recent divorcée. Eva falls in love unexpectedly and discovers her new love interest is the ex-husband of her friend. To date, Enough Said is Holofcener’s most financially successful film. The film was officially released on September 20, 2013, a few months after Gandolfini’s death.

In 2015, it was announced that Holofcener was set to direct an adaptation of Lee Israel’s memoir Can You Ever Forgive Me?, with Julianne Moore in consideration for the lead role. However, later that year, Moore left the project. Eventually Melissa McCarthy was selected for the lead role. The film—ultimately directed by Marielle Heller—was well-received by critics after being released on October 19, 2018, garnering Holofcener an Academy Award nomination and won the WGA awards for the film’s screenplay.