Janney was raised in Ohio and harbored dreams of Olympic skating medals before a freak accident in her senior year of high school dashed her plans. Attending a dance in a strapless gown, someone stepped on her skirt, tearing the dress. In an effort to preserve her dignity, Janney blindly ran—through a glass door. She was severely injured, losing a lot of blood. After recovering, Janney attended Kenyon College and lucked out by landing a role in a play directed by alumnus Paul Newman. Newman's wife, Joanne Woodward, encouraged the young actress and suggested she consider studying at NYC's Neighborhood Playhouse. Despite her credentials (including a stint at London's RADA and work Off-Off-Broadway and in regional theater), Janney had trouble finding an agent due to her height.

The actress eventually landed representation and by the mid-90s, her career began to blossom. In 1994 alone, she appeared in small roles in several films, including "The Cowboy Way" and "Wolf", was featured in the Off-Broadway play "Fat Men in Skirts" and landed a recurring role as a wisecracking maid on the CBS soap "Guiding Light". In the latter, she was partnered with a short blond woman and provided welcome comic relief. More roles followed, yet none fully displayed her abilities until she was tapped by former co-star Stanley Tucci for "Big Night". As Ann, Janney projected the right mix of shyness and longing in her scenes with Shalhoub, with the actors bringing a touching quality to their characters' burgeoning relationship. Later that year, the actress won raves for her Broadway debut as the sophisticated ex-wife of a neurotic matinee idol (Frank Langella) in a revival of Noel Coward's "Present Laughter".

After small roles in 1997's "The Ice Storm" (as the hostess of the key party) and "Julian Po" (as the mayor's wife), Janney returned to the stage in triumph, earning a Tony nomination for her turn as the wife of a longshoreman in Arthur Miller's "A View From the Bridge". She was also seen to good effect as Jennifer Aniston's stepsister in "The Object of My Affection" and as a con woman in "The Imposters" (both 1998). That same year she had a scene-stealing role as the trashy best friend of a Midwestern stage mother in the comedy "Drop Dead Gorgeous" and had similarly memorable turns in "10 Things I Hate About You" and "American Beauty" (both 1999), playing a guidance counselor with romance novelist aspirations in the former and a chronically depressed middle-aged wife of a tyrannical husband in the latter. She returned to the New York stage in 1999, tackling her first major Shakespearean role, starring opposite Jay O Sanders in the New York Shakespeare Festival's production of "The Taming of the Shrew".

Having done remarkable work in such TV-movies as "...first do no harm" (ABC, 1997), "Path to Paradise: The Untold Story of the World Trade Center Bombing" (HBO, 1997) and "David and Lisa" (ABC, 1998), Janney made her primetime series regular debut with a starring turn on the popular and critically lauded NBC political drama "The West Wing". Here she portrayed Press Secretary C J Gregg, professional and composed in action, but emotional and sharp behind the scenes. The smart and feisty but somewhat vulnerable character seemed tailor-made for the actress, who won critical kudos for the series' impressive premiere season. Janney would take home the Emmy for Outstanding Supporting Actress in a Drama Series in 2000 and 2001, then in an upgrade snared the trophies for Outstanding Lead Actress in a Drama Series in 2002 and 2004.

Now a recognizable performer to many Americans, Janney continued to prove her skills with an unforgettable supporting turn as an acerbic soap opera producer in "Nurse Betty" (2000). She was next featured alongside Rebecca DeMornay and Glenne Headley as one of a trio of sisters forced to live together for a week in order to collect an inheritance in the "The Three Sisters" segment of the Showtime anthology special "A Girl Thing" (2001). As she continued to earn accolades for expertly fleshing out her "West Wing" character with show creator Aaron Sorkin, she also continued to make potent supporting turns in major films, including her role as Meryl Streep's lesbian companion in the acclaimed motion picture "The Hours" (2002). In 2003 she took on a slightly larger supporting part, playing Mandy Moore's divorced, embittered mother in the teen romance "How to Deal," and voiced peach the Starfish in the Disney/Pixar's CGI-animated phenomenon "Finding Nemo" (2003). Janney then played the new neighbor of a widower (Anthony LaPaglia) within whom she sparks long lost feelings in the well-reviewed ensemble drama, “Winter Solstice” (2005).