He played in Major League Baseball (MLB) for the Minnesota Twins, Washington Nationals, San Francisco Giants, Tampa Bay Rays and Seattle Mariners.

Span batted and threw left-handed and at the height of his career was known as one of the premier leadoff hitters in baseball due to his exceptional on-base percentage.

Wilson, a Federal City College graduate, supported Span and his brother, Ray, by working variously as a claims adjuster and day care operator.

[6] Span was selected by the Minnesota Twins in the first round (20th overall) of the 2002 Major League Baseball draft from Tampa Catholic.

In 2006, Span returned to the Rock Cats and spent the entire season with the team, batting .285 with two home runs and 45 RBI in 134 games.

[9] He was later promoted to the Triple-A Rochester Red Wings for the 2007 season, and hit .267 with three home runs, 55 RBI and 25 stolen bases in 139 games.

[12] However, on April 5, Michael Cuddyer was placed on the 15-day disabled list and Span was called up to make his Major League debut against the Kansas City Royals the next day.

[16] On April 2, Span collected the first hit (a triple) and the first home run in the Twins' new ballpark Target Field in an exhibition game against the St. Louis Cardinals.

[17] On June 29, Span tied the modern-day Major League Baseball record by hitting three triples in one game against the Detroit Tigers in an 11–4 victory.

[20] After the trade, Span became the team's starting center fielder, moving 2012 NL Rookie of the Year Bryce Harper to left field.

[23] Span finished the 2014 season hitting .302/.355/.416 with five home runs, 37 RBI and a career-high 31 stolen bases in 147 games.

[10] On December 20, 2017, the Giants traded Span, Christian Arroyo, Matt Krook, and Stephen Woods to the Tampa Bay Rays for Evan Longoria and cash considerations.

[30] On March 29, 2018, Span hit a three-run triple on Opening Day 2018 against Carson Smith of the Boston Red Sox to give the Rays a 5–4 lead.

[10] On May 25, 2018, the Rays traded Span and reliever Álex Colomé to the Seattle Mariners in exchange for minor leaguers Andrew Moore and Tommy Romero.

[10] On January 24, 2021, it was announced that Span was hired by the Tampa Bay Rays as a special assistant in baseball operations.

[38] Span proposed to Anne Schleper, who won a silver medal for ice hockey with the United States in the 2014 Winter Olympics, on December 31, 2016.