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Guthrie was born on April 8, 1979, in Roseburg, Oregon. He grew up in Ashland, Oregon. In high school, he played multiple sports, including baseball, football, and basketball. He was also class valedictorian. He also earned Eagle Scout rank with the Boy Scouts of America. Guthrie attended Brigham Young University and Stanford University, where he was a starting pitcher. He served a two-year mission for the LDS Church to Spain. He passed on an offer by the New York Mets in order to serve his mission.
Guthrie is 6'1" tall and weighs 205 lbs. His 2011-2012 contract status for one year was $5.75 million.
Guthrie spent most of the 2006 pro-ball season with the Triple-A Buffalo Bisons, but was twice called up to the majors to join the Cleveland Indians as a relief pitcher.  On January 19, 2007, Guthrie was designated for assignment and was picked up by the Baltimore Orioles. Later that year, Guthrie had become one of the best pitchers in the American League. This put him into consideration for the Rookie of the Year Award.
During the 2008 season, Guthrie emerged as the staff ace of the Baltimore Orioles. Guthrie pitched for Team USA in the 2009 World Baseball Classic.
On January 2012, he was traded to the Rockies, and then in July, he was traded to the Royals. In November of that year, he signed a three-year, $25 million contract with the Royals. In January 2014, the Royals reworked their contract with him by adding a $10 million mutual option for 2016. During the 2014 World Series, Guthrie pitched the Royals to victory in game 3.
On May 25, 2015, Guthrie had the worst start of his career in the game against the New York Yankees. He gave up 9 hits, 11 earned runs, 3 walks. 13 of the 16 batters he faced reached base, and he recorded just 3 outs before being pulled. By August, the Royals had demoted him to the bullpen to make room for Kris Medlen in the rotation. On February 20, 2016, he signed with minor league Texas Rangers.
In the off-season, Guthrie lives with his wife, Jenny, and children in Pleasant Grove, Utah. He is an avid believer in living green, bicycles to work and recycles everything possible.  He is also an avid fan of fast food and considers Utah Valley the fast food capital of the world.
Guthrie is a shoe aficionado. He has over 400 pairs and is fascinated with their design and marketing. On April 28, 2014, he unveiled Nike Foamposite baseball cleats in the game against the Baltimore Orioles. He would like to play baseball in Japan, the homeland of part of his heritage. When he retires from baseball, he hopes to work for Nike.