He began his major league career in 1998 with the St. Louis Cardinals, and also played for the Atlanta Braves, Los Angeles Dodgers, and Boston Red Sox.

He set a Florida State record by batting .455 in 1997 while becoming one of only three players in college baseball history to have 100 hits, 100 runs and 100 RBIs.

The Phillies had no plan to pay an unproven player this amount of money, and despite Boras' warnings, drafted Drew nonetheless.

He was recalled by the Cardinals and made his debut on September 8, 1998—the game in which teammate Mark McGwire broke the single-season home run record previously held by Roger Maris.

In an attempt to confuse the Philadelphia fans, he did not wear his own jersey that night, which instead was worn by bullpen catcher, Jeff Murphy.

The only time he received cheers was when he booted three consecutive grounders in the outfield while his teammates were taking batting practice.

[7] On August 10, 1999, in Drew's first game at Veterans Stadium in Philadelphia, he was booed loudly, and even had batteries thrown at him by two fans.

The Phillie Phanatic got into the act, dropping two large trash bags marked with dollar signs in the outfield between innings.

In his book Three Nights in August, Buzz Bissinger mentions former manager Tony La Russa's frustration with Drew's lack of passion.

La Russa tells Bissinger that it seems Drew had decided to "settle for 75%" of his talent, in large part because of his enormous contract.

In 2004, he displayed excellent power, patience, and defense, hitting .305 with 31 home runs, 118 walks, and 93 RBI, finishing sixth in the MVP voting.

In December 2004, Drew signed a five-year, $55 million contract with the Los Angeles Dodgers,[12] which included an escape clause after the second year.

On September 18, 2006, Drew was part of only the (then) fourth-ever set of back-to-back-to-back-to-back home runs with fellow Dodgers Jeff Kent, Russell Martin, and Marlon Anderson.

[16] Drew was again part of a set of four consecutive home runs on April 22, 2007, in a game against the New York Yankees, this time joining with Manny Ramírez, Mike Lowell, and Jason Varitek.

[18] On October 20, 2007, Drew hit a grand slam in Game 6 of the 2007 ALCS with the Red Sox facing elimination.

[23] On October 16, in Game 5 of the American League Championship Series against the Tampa Bay Rays, Drew helped to bring the Red Sox back from a late-inning seven-run deficit with a two-run home run in the eighth inning and then delivered the walk-off hit in the ninth.