Clark played college basketball at the University of Arizona and San Diego State, where he was the Aztecs' top scorer with 11.5 points per game in 1991–92. During the summers, he played minor league baseball after having been drafted out of high school with the second overall pick in 1990 by the Detroit Tigers. He would eventually leave college (and his basketball career) without finishing his Business administration degree in order to focus on baseball.

Clark had his best years with the Detroit Tigers (1995–2001), but also played with five other teams during a 15-year career that ended in 2009. He was a switch hitter, and threw right-handed. He was third in Rookie of the Year voting in 1996, and was an All Star in 2001.

He was third in Rookie of the Year voting in 1996, when he hit .250 with 27 home runs.

His most productive seasons were 1997, with 32 homers and 117 RBIs (10 errors at first base), 1998, with 34 homers and 103 RBIs (13 errors at first), and 1999, with 31 home runs and 99 RBIs (10 errors at first).

Throughout his playing career, Clark was involved in the Major League Baseball Players Association (MLBPA) on various levels. He attended an Executive Board meeting for the first time in 1999 and was a team player representative and Association Representative for several seasons following. He was an active participant in the union's collective bargaining in 2002 and 2006 and in negotiations regarding Major League Baseball's drug policy. In March 2010, Clark was hired to be the MLBPA's Director of Player Relations.

In 2002, Clark hit only .207 with 29 RBIs and three home runs for Boston in 90 games, with a career-low .291 slugging percentage. In 2003, he batted .232 for the New York Mets.

Clark signed with the Arizona Diamondbacks after the 2004 season. In 2005, he enjoyed success with the D-Backs. In a limited role (349 at bats), he hit .307, belted 30 home runs, and knocked in 87 runs.

In 2006, Clark was injured for most of the season. Although he tried to play through a shoulder injury that required significant surgery to repair, he batted a career-low .197, with a career-low .279 on-base percentage, in 132 at-bats. He struggled especially against right-handers, batting .125 against them.

In 2007, Clark shared first base with Conor Jackson. He played in 113 games, and batted .249.

Clark played in four post-season series through 2008, two each for the Yankees and the Diamondbacks. In aggregate, he batted .135, with a .158 on-base percentage and a .189 slugging percentage, and drove in one run in 37 at-bats.

In August 2009, after being released from the Diamondbacks, Clark became a studio analyst with the MLB Network.

Clark was a union representative while he was a player, and after retiring he joined the staff of the MLBPA in 2010. He served as deputy executive Director and acting executive Director of the union before he was appointed executive Director in December 2013, upon the death of Michael Weiner. Clark is the first former player to be executive Director of the MLB players' union.

It was reported in April 2013 that Clark was close to earning a degree in history and planned to potentially pursue a law degree. Following the death of Michael Weiner, Clark was unanimously voted executive Director of Major League Baseball Players Association in December 2013. He became the first former Major League player to hold the position.