Despite playing in fewer than five full seasons for the team, Greene is the Padres' career leader in home runs at the shortstop position.

[1] Greene was raised by his father, James, a woodworker, and mother, Janet, a schoolteacher, in the Baháʼí Faith.

[6][7][8] Greene again started every game for the Clemson Tigers in his junior season, but this time he and erstwhile shortstop Jeff Baker switched positions.

Peter Gammons made a prediction in his 2001 pre-draft column on ESPN.com: "You won't find Clemson shortstop/third baseman Khalil Greene or Wake Forest center fielder Cory Sullivan on any top-100 list, but check back in five years from now and see if they aren't remarkably like Jeff Cirillo and Steve Finley.

Greene's senior season was his most impressive: Collegiate Baseball named him National Player of the Year.

[9] After Greene finished the 2002 season, having graduated with a bachelor's degree in sociology, he held school single-season records for total bases, extra-base hits, home runs, RBI, consecutive multi-hit games, and consecutive games with a home run.

Greene was taken by the San Diego Padres with the thirteenth pick of the 2002 Major League Baseball Draft.

[10] After finishing his college career and being drafted by the Padres, Khalil Greene reported to the Single-A Eugene Emeralds where he played only ten games.

Greene saw his first major league action on September 3, 2003, where he came into the game as a pinch-hitter for Brian Lawrence in the seventh inning and flew out against the Arizona Diamondbacks.

His first home run led off the eighth inning of the September 16 game against Jerome Williams of the San Francisco Giants.

In 2006, Greene appeared in 121 games, and had 101 hits in 412 at-bats (.245) with 15 home runs and 55 RBI, helping the Padres win their second consecutive National League West title.

On July 30, 2008, Greene broke his hand due to punching a storage box after striking out for the 100th time that season[citation needed] (with his batting average dropping to .213).

On December 4, 2008, Greene was traded to the St. Louis Cardinals for Mark Worrell and a player to be named later; he made $6.5 million in 2009.

Playing third base for the first time since college, he went 2-for-2 with a double, a solo home run and a walk, eventually being substituted after fouling a ball off his foot.

Following a 1-for-17 stretch over five games, Greene was placed back on the disabled list with social anxiety disorder on June 29.

[14] On February 22, 2010, he announced that he had been suffering another episode of social anxiety disorder, and that he would not be reporting to Rangers spring training.