Guillén was signed by the Houston Astros as a non-draft amateur free agent in 1992. He was traded to the Seattle Mariners with pitcher Freddy García and John Halama in the deal that sent Randy Johnson to the Astros. Guillén made his debut in 1998 and was traded to Detroit at the end of the 2003 season.
In Seattle, Guillén was initially forced to play second and third base with incumbent Alex Rodriguez at shortstop. After Alex Rodriguez signed with the Texas Rangers for the Template:By season, Guillén moved back to his natural position. He had a league-average campaign in his first full season with the club.
In Game 3 of the 2000 American League Division Series, he hit a squeeze play in the bottom of the ninth inning to score Rickey Henderson and complete the Mariners' sweep of the Chicago White Sox. In September 2001, Guillén was hospitalized after being diagnosed with pulmonary tuberculosis, but was ready for the American League Championship Series against the New York Yankees the following month.
In Template:By, Guillén joined a young and restructured Tigers team. In a career year, he led his club in RBI (97), runs (97), doubles (37), triples (10), total bases (283), slugging percentage (.542), OPS (.921), and his .318 batting average was only second to .334 of teammate Iván Rodríguez. Guillén also got his first All-Star berth. However, his breakout season was cut short, as he missed the final month of the 2004 season after tearing his ACL while legging out a triple.
He healed well during the 2004 05 offseason and was back to his previous form in time for Template:By's opening day, although problems with his left hamstring kept him out of the lineup for much of the year.
Guillén returned to elite status in Template:By having another outstanding season. His on-base percentage reached .400 for the first time in his career, and he led all Major League shortstops with a .919 OPS.
In 2006, Guillén became the first player in modern Major League history to raise his average for six consecutive seasons, batting .320. In the field, however, he tied for the major league lead in errors at shortstop, with 28.
On August 6, 2007, he got his 1,000th hit, knocking in Curtis Granderson with two out in the bottom of the first.
On September 30, 2007, on his 32nd birthday, Guillén hit the 93rd home run of his career and it gave him 100 RBIs in a season for the first time in his career.
Due to the acquisition of shortstop Edgar Rentería from the Atlanta Braves during the 2007–2008 offseason, and due to his decreased mobility, Guillén initially moved to first base to start the 2008 season. However, on April 22, manager Jim Leyland announced that Guillén would be moving to third base, with Miguel Cabrera becoming the new starting first baseman.
Jim Leyland has announced Guillén will play left field again in 2010 if he stays healthy, but Guillén has publicly stated he would prefer to play third base or shortstop. 
In May 2010, it was announced that Guillén would be the Tigers 2nd baseman after returning from a hamstring injury which he suffered on April 23, replacing rookie Scott Sizemore.
Guillén has three children with his wife Amelia—two sons and a daughter.
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