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 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.

He healed well during the 2004 05 offseason and was back to his previous form in time for 2005's opening day, although problems with his left hamstring kept him out of the lineup for much of the year.

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.

[3] 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.

Weaver was upset about Magglio Ordóñez hitting a home run off of him earlier, and quipped to Tigers first baseman Miguel Cabrera that he was "an asshole" about the situation.

Weaver was eventually ejected after throwing a high fastball in retaliation at the head of the following batter, Detroit catcher Alex Avila.