Holmes was born in Bowling Green, Ohio and is the daughter of Dr. John Holmes and Judith A. Holmes. Her father is thrice a Fulbright Scholar, and part of the International Advertising Association, World Conference of Education and the United Nations. Holmes’ parents divorced in 1979, and Holmes moved out west with her older brother, sister and mother to San Diego, where Judith taught as an English teacher and San Diego County Office of Education Reading Specialist, helping children with learning disabilities to read.
Holmes graduated from the University of San Diego High School, was a cheerleader and on the honor roll. She was voted by her class, in the "senior standouts" as the person most desired as "deserted island companion". Holmes was discovered at the age of 16, while dining in a restaurant in Manhattan and sitting at a table next to Jodie Foster. Fashion photographer Marco Glaviano approached Susan and asked if she was a model. After meeting various top agents, Holmes was accepted by two modeling agencies, Ford and Elite. It was at the age of 17, that Holmes was on her first cover of a magazine (San Diego magazine) and also appearing in ads on billboards.
Holmes' designer accomplishments stem from a career as an international model. Holmes worked for Dior, Dolce & Gabbana, Valentino, Chanel, Versace, John Galliano, Christian Lacroix, Herve Leger, Badgley Mischka, Nicole Miller, Marc Jacobs, and Prada. Holmes also has appeared in ad campaigns for Yves Saint Laurent, Fendi, Escada, Guess, Revlon, Karl Lagerfeld, Louis Vuitton, and Victoria's Secret. Holmes was in television commercials for Peugeot (which actually won an award and was filmed by Madonna videographer Jean-Baptiste Mondino). She then followed with two more commercials, for Triumph and H&M lingerie. Susan then starred as "the runaway bride" alongside fellow models Tyra Banks, Kate Moss, and Helena Christensen in the British film Inferno! She has appeared on the covers of Vogue, Elle, Marie Claire, Playboy and Australian Maxim.

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