Her portrayal of Jill St. Claire in The Whole Nine Yards (2000) brought her wider recognition,[2] and she has since appeared in a variety of films, including Saving Silverman (2001), High Crimes, Changing Lanes, Igby Goes Down (all 2002), Something's Gotta Give, Identity (both 2003), Melinda and Melinda (2004), A Lot like Love, Syriana (both 2005), The X-Files: I Want to Believe (2008), 2012 (2009), Gulliver's Travels (2010), Identity Thief, and The Way, Way Back (both 2013).

Outside of film, Peet played Jacqueline Barrett on The WB's Jack & Jill (1999–2001), Jordan McDeere on NBC's short-lived Aaron Sorkin series Studio 60 on the Sunset Strip (2006-2007), Tina Morris on HBO's Togetherness (2015–2016), Jules on IFC's Brockmire (2016–2020), Betty Broderick on the second season of Bravo's Dirty John (2020), and Beth Gallagher in the Paramount+ adaptation of Fatal Attraction (2023).

[10] Peet's first screen performances were in a television commercial for Skittles and an uncredited appearance as the girlfriend of the titular character in the second episode of The Larry Sanders Show in 1992.

Peet appeared in the critically acclaimed film Playing by Heart (1998), as part of an ensemble cast that included Sean Connery, Angelina Jolie, and Ryan Phillippe.

[12][13] Peet appeared alongside Bette Midler and Nathan Lane in Andrew Bergman's Isn't She Great (2000), a highly fictionalized account of the life and career of author Jacqueline Susann.

Peet took on the role of a psychologist and the romantic interest of Jason Biggs in the comedy Saving Silverman (2001),[17][18] and portrayed a heroin-addicted trophy mistress in the dramedy Igby Goes Down, which garnered acclaim among critics.

In 2003, Peet appeared with Diane Keaton, Jack Nicholson and Keanu Reeves in the romantic comedy Something's Gotta Give, directed by Nancy Meyers, playing an auctioneer, working for Christie's.

[22] Her most significant film role in 2005 was that of a woman who becomes a successful photographer, opposite Ashton Kutcher, in the romantic comedy A Lot Like Love, which revolved around two people whose relationship slowly evolves from lust to friendship to romance over the course of seven years.

In 2006, Peet acted on Neil Simon's Broadway production of Barefoot in the Park, followed by the romantic drama Griffin & Phoenix, a remake of the 1976 ABC TV movie, in which she portrayed a terminally ill woman living life to the fullest.

What Doesn't Kill You was her best reviewed film of 2008,[27] with Lisa Schwarzbaum of Entertainment Weekly, writing that Peet "is terrific as Brian's worn-down wife, sick of seeing her man disappear before her eyes.

In 2013, she made her playwriting debut with The Commons of Pensacola, starring Blythe Danner and Sarah Jessica Parker,[43][44][45] and appeared in the film Identity Thief, as the wife of a man whose identity is stolen by a woman, the little-seen comedy Trust Me, as the neighbor of a former child star, and the well received dramedy The Way, Way Back, as one half of a married couple.

[46][47] IndieWire called it "the upbeat comedy HBO needs right now", and noted that while Lynskey is "the true standout", Peet "won't be short of fans".

[49] In 2021 Netflix released The Chair, a six-episode comedic dramatic series written by Peet and produced by her, alongside David Benioff and D. B.

[51] Peet's comments stirred controversy; in response, she apologized for using the term "parasites," but affirmed her position on the importance and safety of vaccinations.

[54] Peet has co-written a children's book Dear Santa, Love, Rachel Rosenstein about a Jewish girl during the Christmas season.

[55] Peet also wrote a play Our Very Own Carlin McCullough, which ran for two months in 2018 at the Geffen Playhouse in Los Angeles to positive reviews.

[56] Peet married screenwriter David Benioff, son of former Goldman Sachs CEO and chairman Stephen Friedman, on September 30, 2006, in New York City.