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Iles was born in Stuttgart, Germany, where his physician father ran the U.S. Embassy Medical Clinic. He was raised in Natchez, Mississippi, the setting of many of his novels. After attending Trinity Episcopal Day School, he graduated from the University of Mississippi in 1983. Iles spent several years as a guitarist, singer, and songwriter in the band Frankly Scarlet. He quit the band after he was married and began working on his first novel, Spandau Phoenix, a thriller about Nazi war criminal Rudolf Hess. Spandau Phoenix was published in 1993 and became the first of twelve New York Times best sellers. In 2010 The Devil's Punchbowl reached #1 on the Times list.
Iles has published thirteen novels in a variety of genres. His books have been translated into more than twenty-five languages and published in more than thirty-five countries worldwide.
In 2002, he wrote the script 24 Hours from his novel of the same name. It was rewritten by director Don Roos and renamed Trapped (to avoid confusion with the then-current television series, 24), which Iles then rewrote during the shoot, at the request of the producers and actors. Iles has mixed feelings about the film, but he enjoyed working with the actors, including Charlize Theron, Kevin Bacon, Courtney Love, and Dakota Fanning.
In 2011, Iles sustained life-threatening injuries in a traffic accident and ultimately lost part of his right leg. He has since recovered and is now finishing a trilogy of novels featuring Penn Cage which is set in Natchez, Mississippi, Iles's hometown. The first volume is titled "Natchez Burning" and will be published in April 2014.
Iles is a member of the literary musical group The Rock Bottom Remainders, which includes authors Dave Barry, Ridley Pearson, Stephen King, Scott Turow, Amy Tan, Mitch Albom, Roy Blount, Jr., Matt Groening, and James McBride. In July 2013, Greg co-authored Hard Listening (2013) with the rest of the Rock Bottom Remainders. The ebook combines essays, fiction, musings, candid email exchanges and conversations, compromising photographs, audio and video clips, and interactive quizzes to give readers a view into the private lives of the authors/musicians.