Stairs began his major league career with the Montreal Expos during 1992 and 1993.  Over the next ten years, Stairs played for the Red Sox, Athletics, Cubs, Brewers, and Pirates. In his season with the Pirates (2003), Stairs had the best batting average of his career - .292, and hit 20 homeruns while driving in 57 runs. The following year, he signed with the Kansas City Royals and enjoyed a three year stint with them. 

During the 2006 season, he split the year between the Texas Rangers and the Detroit Tigers, in which he helped them win the AL Wild Card. The next two years were spent with the Blue Jays, where Stairs saw significant increase in playing time which resulted in his higher performance. In August of 2008, Stairs was traded to the Phillies. 

He hit is first career post-season homerun on October 13 in Game 4 of the NL Championship Series, helping lift the Phillies to victory and advance to the World Series. Stairs won his first World Series ring in 2008 and would later return to the 2009 World Series with the Phillies once again, this time they fell short though.

In 2010 and 2011, he spent with the Padres and Nationals respectively.  On August 3rd, 2011 Stairs announced his retirment after his 19 year career. At the time of his retirement, he held the record for most pinch-hit homeruns in MLB history with 23.