Newsom and Guilfoyle married in a lavish ceremony in 2001, with a 500 person reception held at Ann and Gordon Getty's home. In 2003, Newsom was elected mayor of San Francisco. At the same time, Guilfoyle's star was on the rise, as she drew notice for her work on the murder trial over the death of Diane Whipple. In 2004, Guilfoyle became the host of the CourtTV show Both Sides, which filmed in New York City. Guilfoyle moved to the East Coast, while Newsom remained in San Francisco.

Despite the distance, the couple was featured in several magazine profiles, including a Harper's Bazaar piece which compared them to the Kennedys' Camelot years. However, there was trouble beneath the surface of their relationship. In 2005, the couple announced they would be filing for divorce, blaming the split on the bicoastal distance. Additionally, Guilfoyle's friends claimed that, despite her high profile wedding, she had "never signed on" to be the wife of a mayor.