Graham was born an only child on March 16, 1967 in Honolulu, HI, but raised in northern Virginia after her parents divorced. Her dad, Lawrence, took a lobbyist position in Washington, D.C. and raised her on his own, while her mom, Donna Grant, remarried and moved to England. After attending Langley High School in Virginia where she was involved in competitive horseback riding, Graham began performing while an undergraduate with the a cappella/comedy troupe the Metronomes. After majoring in English at Barnard and graduating with a Master of Fine Arts from Southern Methodist University in Dallas, TX, Graham moved to New York, where she landed an agent and began working steadily ever since. After a few stage appearances, she relocated to Los Angeles in 1995 and was cast in the recurring role of Shelley, the perky but needy girlfriend of artist Richard Karinsky on the sitcom, “Caroline in the City” (NBC, 1995-99).

Graham was offered her first regular as a young, ambitious copywriter on "Good Company" (CBS, 1995-96), an ensemble sitcom that followed the professional and personal lives of the creative team of a mid-Manhattan advertising agency. After that series came and went, she was cast as a new mom and bride-to-be who waitresses with a group of twentysomething New England women in "Townies" (ABC, 1996-97). While most praised the shows three female leads (Graham, Jenna Elfman and Molly Ringwald), Graham was singled out for her skill in negotiating her character's mercurial moods. Once again, however, Graham’s show failed to stay on air long enough for audiences to get to know her. Following a three-episode guest arc on "Law & Order" (NBC, 1990- ) and a subsequent one-shot as Jerry Seinfeld's speed-dial-obsessed girlfriend on "Seinfeld" (NBC, 1988-98), Graham won kudos for her playing the perky but ruthless efficiency expert Andrea in a recurring role on the NBC sitcom "NewsRadio" during the 1997-98 season.

Graham segued to the big screen in a supporting role in "Nightwatch" (1998); then landed a larger part as a soap opera actress in the independently made "Confessions of a Sexist Pig" (1998). She rounded out the year by appearing in support of Renee Zellweger in "One True Thing" and returning to series TV as Molly, the former girlfriend, now best buddy of an advertising executive on "Conrad Bloom" in the short-lived 1998 NBC sitcom. In 1999, she appeared opposite Billy Burke as the title character's girlfriend in "Dill Scallion," director Jordan Brady's low-budget mockumentary about a country-music star that steadily gains a devoted cult following over the years.

When she found out that she had been hired for ''Gilmore Girls'' in 2000,Graham was headlining a short-lived NBC show called ''M.Y.O.B.'' as Opal Marie Brown, a high school administrator trying to keep the lid on a rebellious niece. She was hired in ''second position'' for ''Gilmore Girls'' – meaning the producers would have to recast if ''M.Y.O.B.,'' to which she was legally bound, was picked up for a full season. Luckily the sitcom bombed after only five airings. Free to move forward with "Gilmore Girls," Graham finally found the perfect star vehicle for all of her comedic strengths, as well as her inherent ability to relate. Playing the fast-talking but financially struggling 30-ish mom Lorelai, who has to turn to the wealthy, proper and hypercritical parents whom she has been estranged from for 16 years in order to fund her bright daughter's education, Graham and her young co-star Alexis Bledel struck a chord with viewers – the warm, family-friendly but never saccharine "Gilmore Girls" became one of the WB's most reliable ratings-grabbers. The role would also earn Graham a Family Television Award as Best Actress, as well as nominations from the Golden Globes and Screen Actors Guild awards.

Thanks to the success of "Gilmore Girls" Graham continued to land movie roles as her schedule allowed, appearing in the indie romantic comedy "Lucky 13" and as Keanu Reeves' girlfriend in "Sweet November" (2001). Throwing her TV image aside, she had a memorable turn romping with a seedy Billy Bob Thornton as the sex-crazed department store Santa groupie Sue in director Terry Zwigoff's gleefully cynical comedy, "Bad Santa" (2003). She also played a high school principal who clashes with Navy SEAL-turned-government babysitter Vin Diesel in the surprising hit Disney comedy, "The Pacifier" (2005). In 2007, after months of speculation in the media, “Gilmore Girls” was finally canceled when both Graham and Bledel felt it was time to move on. Meanwhile, Graham continued making a name for herself in high profile features like “Evan Almighty” (2007), playing the concerned wife of newly minted U.S. Congressman Evan Baxter (Steve Carell) who is anointed by God (Morgan Freeman) to build an ark to prepare for a coming flood, while learning a thing or two about the value of helping others.