Zuniga was born in San Francisco, California to Agnes A. Zuniga (née Janawicz) and Joaquin Alberto Zuniga Mazariegos. Her mother is a Unitarian minister, of Polish and Finnish descent, and her father, originally from Guatemala, was an emeritus professor of philosophy at California State University, East Bay. Zuniga has two sisters: Jennifer Zuniga and Rosario Zúñiga.
In her early teens, Zuniga expressed interest in acting, and attended the Young Conservatory program of the American Conservatory Theater of San Francisco. After her parents divorced, Zuniga moved with her mother and sister from Berkeley, California to Reading, Vermont, where she spent the remainder of her teenage years. Zuniga graduated from Woodstock Union High School in Woodstock, Vermont, in 1980, after which she returned to California and enrolled at the University of California, Los Angeles to study theater arts. After leaving college, Zuniga was close friends and roommates with fellow actress Meg Ryan.
Zuniga made her film debut in a supporting part in the slasher film The Dorm That Dripped Blood (1982), while a student at the University of California, Los Angeles. She was then cast in the 1984 horror film The Initiation (1984), opposite Vera Miles and Clu Gulager. This was followed by a lead role, opposite John Cusack, in Rob Reiner’s film, The Sure Thing (1985).
In 1986, she starred as Princess Vespa in Mel Brooks’ memorable cult comedy Spaceballs (1987), followed by a supporting part in the science fiction horror sequel, The Fly II (1989). From 1992 to 1996, Zuniga portrayed Jo Reynolds on the wildly popular soap opera Melrose Place (1992), which garnered Zuniga wider mainstream exposure. Her role on the series would be followed by numerous appearances on television series, including a lead role as Shelly Pierce on American Dreams (2004) from 2004 to 2005, and a recurring on the popular CW series, One Tree Hill (2003), as Victoria Davis, a role which she played from 2008 until 2012.
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