Glaus began his career with the Angels in 1998 and was installed as the team’s starting third baseman in 1999.

Glaus had a breakout season in 2000, becoming the all-time single season home run leader in Angels history with 47 while leading third baseman in adjusted range factor (2.95) in 2000.

Glaus participated in the 2001 MLB All-Star Game and posted his second consecutive 40 home run season with 41 on the year.

In 2002, Glaus failed to reach the 40 home run club for the first time since the 1999 season, but he managed to hit thirty home runs in helping the Angels make the playoffs for the first time in 16 years. The Angels beat the San Francisco Giants in 7 games to win their first World Series title in team history.

Glaus followed that up with another All-Star year in 2003.

Glaus worked through his back problems in the 2005 season, with the Diamondbacks, by hitting 37 HRs (tops amongst 3Bs) with 97 RBIs. He also led the league in adjusted range factor (2.92), but his 24 errors tied him with David Wright for the most errors by a third baseman in the Major Leagues, and he had a Major League-low .946 fielding percentage at third. He was traded to the Toronto Blue Jays in the off-season along with minor league shortstop Sergio Santos. The trade sent pitcher Miguel Batista and second baseman Orlando Hudson to the Diamondbacks. The Jays badly needed a power bat a year after letting go of Carlos Delgado, however the emergence of Hudson at second base gave the statistical advantage of this trade to the Diamondbacks.

Although Glaus was converted from shortstop to third base in the minors (and played 10 games at shortstop for the Angels), he started at shortstop for the Toronto Blue Jays against the Chicago White Sox on May 26, 2006 due to the demotion of shortstop Russ Adams. Glaus was not expected to do much fielding due to the fact the pitcher that day was known to induce many fly balls, instead of ground balls. This defensive alignment didn’t affect his hitting, collecting 2 hits with a home run. Since then, Glaus made several starts at shortstop, usually when Toronto was facing National League opponents at their home ballpark, where there is no DH.

After hitting 38 home runs and 104 RBI in the 2006 season, Glaus earned a single 10th place vote for the 2006 American League MVP Award.

In 2006, Glaus had the lowest zone rating of any Major League third baseman (.741).

In 2007 Glaus’s production was hampered all year by foot injuries and his production fell.

On December 13, 2007, he was cited in the Mitchell Report.

Glaus was traded to the St. Louis Cardinals in exchange for fellow third baseman Scott Rolen on January 14, 2008. This worked out well for the Cardinals, as Glaus did about as well as, or better than, his career rates in most offensive categories. Furthermore, Glaus committed only 7 errors in 146 games and led the league with a .982 fielding percentage at 3B.

On September 3, 2008, he hit his 300th career home run off Doug Davis of the Arizona Diamondbacks in the third inning.

He underwent arthroscopic right shoulder surgery on January 21, 2009. The Cardinals initially expected him to be ready around the start of 2009 season, but after a setback in his rehabilitation he was placed on the 15-day DL; after another reassessment the Cardinals announced that they did not expect him to return until June 2009. On July 11, 2009 he was assigned to the Palm Beach Cardinals of the Florida State League on a rehabilitation assignment. He returned September 2, against the Brewers in the bottom of the 6th inning.

Following an injury-shortened 2009 season with the St. Louis Cardinals, Glaus signed a one-year $1.75 million contract with the Atlanta Braves, a deal that allows him to earn an additional $2.25 million in performance and roster bonuses. He became the starting first baseman in 2010.

Glaus became a candidate for induction into the National Baseball Hall of Fame and Museum for the first time on November 9, 2015. He received no votes.