In addition to her work on Generations and Melrose Place, Rutherford also starred in the early 1990s Homefront as Judy Owen, in 1995's The Great Defender as Frankie Collet, in 1996's Kindred: The Embraced as Caitlin Byrne, in 2003's Threat Matrix as Special Agent Frankie Ellroy Kilmer, and had a recurring role in The Adventures of Brisco County, Jr. as Dixie Cousins. She also had a small role on Scream 3 in 2000. Most recently, Rutherford starred as Samantha "Sonny" Liston, on the cancelled TV series E-Ring. Rutherford currently stars as Lily van der Woodsen in The CW hit teen drama Gossip Girl.

Rutherford was born in Elizabethtown, the seat of Hardin County, in central Kentucky. She is the daughter of Ann Edwards, a model and writer, who is divorced from Rutherford's father. She has a younger brother, Anthony, and two younger sisters, Courtney and Lindsey.

Rutherford was married to Carlos Tarajano from June 30, 2001, to January 11, 2002.

Rutherford married her second husband, German businessman Daniel Giersch, in August 2006. She gave birth to their first child, a boy named Hermés Gustaf Daniel Giersch, on October 18, 2006. Rutherford delivered their second child, a girl named Helena Grace Rutherford Giersch, on June 8, 2009. Both children were born at Cedars-Sinai Medical Center in Los Angeles. On December 30, 2008, Rutherford filed for divorce from Giersch. She cited irreconcilable differences on the paperwork, which was submitted to a judge at Los Angeles Superior Court.