In 1989, 15-year-old Cruz made her acting debut in a music video for the Spanish pop group Mecano's song "La Fuerza del Destino". Between 1990 and 1991, she hosted the Spanish TV channel Telecinco's talk show La Quinta Marcha, a programme that was hosted by teenagers, aimed at a teenage audience. She also played in the "Elle et lui" episode of an erotic French TV series called Série rose in 1991, where she appeared nude. In 1992, Cruz made her feature film debut at 18 as the lead female role in the comedy drama art house film, Jamón, jamón. In the film, she portrayed Silvia, a young woman who is expecting her first child with a man whose mother does not approve of the relationship and attempts to sabotage it by paying Javier Bardem's character to seduce her. People magazine noted that after Cruz appeared topless in the film, she became "a major sex symbol". In an interview with the Los Angeles Daily News in 1999, Cruz commented that "it was a great part, but. . . I wasn't really ready for the nudity. [. . . ] But I have no regrets because I wanted to start working and it changed my life. " Charlie Rose of 60 Minutes noted that Cruz "became an overnight sensation as much for her nude scenes as for her talent". When Rose asked Cruz if she was concerned about how she would be perceived after her role in the film, Cruz replied, "I just knew I had to do the complete opposite. "
Cruz has modelled for Mango , Ralph Lauren and L'Oréal . Penélope and her younger sister Mónica Cruz have designed clothing for Mango. Cruz has volunteered in Uganda and India , where she spent one week working with Mother Teresa ; she donated her salary from The Hi-Lo Country to help fund the late nun's mission.
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Cruz is the 11th woman to be given the title by the magazine. Previous honorees include Angelina Jolie, Halle Berry, Rihanna, Charlize Theron and Scarlett Johansson.