In 1984, Janssen moved to the United States to begin her professional career as a fashion model. She signed with Elite Model Management and worked for Yves Saint Laurent, Chanel, and Victoria's Secret. She starred in a 1988 commercial for the perfume Exclamation by Coty, Inc. Her looks have been compared to Hedy Lamarr and other 1940s films stars.
After retiring from modelling in the early 1990s, Janssen had guest roles on several television series, including a starring role in the 1992 Star Trek: The Next Generation episode "The Perfect Mate", as empathic metamorph Kamala, opposite Patrick Stewart, with whom she later starred in the X-Men film series. That same year, Janssen was offered the role of Jadzia Dax in Star Trek: Deep Space Nine, but turned it down to pursue film roles. Her first film role was alongside Jeff Goldblum in the 1992 crime drama film Fathers & Sons.
In 1995, Janssen appeared in Pierce Brosnan's first James Bond film, GoldenEye, as femme fatale Xenia Onatopp. She also appeared in Lord of Illusions with Scott Bakula. In an attempt to fight against typecasting after her Bond girl performance, Janssen began seeking out more intriguing support roles, appearing in John Irvin's City of Industry, Woody Allen's Celebrity, Robert Altman's The Gingerbread Man, and Ted Demme's Monument Ave. Denis Leary, her co-star in Monument Ave., was impressed by how easily she blended in, initially not recognizing her as she was already in character. In the late 1990s, she also appeared in The Faculty, Rounders, Deep Rising, and House on Haunted Hill.
In 2000, Janssen played superheroine Dr. Jean Grey/Phoenix in X-Men. She reprised the role in X2 (2003) and X-Men: The Last Stand (2006), for which she won a Saturn Award for Best Supporting Actress. In addition, Janssen had a prominent role in the second season of the popular TV series Nip/Tuck, as the seductive and manipulative life coach Ava Moore, which earned her Hollywood Life's Breakthrough Artist of the Year Award. She reprised her role in the final two episodes of the series.
In 2007, she starred in Turn the River, for which she was awarded the Special Recognition Best Actress Award at the Hamptons International Film Festival. The following year, she starred in Luc Besson's Taken. Janssen also continued to work in television, appearing in TV pilots for NBC's cop drama Winters and Showtime's The Farm, a The L Word spin-off set in a women's prison. Both pilots were rejected by their respective networks. Janssen also provided the Dutch-language narration for the Studio Tram Tour at all Disney theme parks.
In 2011, Janssen made her directorial début with the drama Bringing Up Bobby. She also wrote the screenplay to the film, which stars Milla Jovovich, Bill Pullman, and Marcia Cross.
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