On February 5, 2008, the Boston Red Sox signed veteran first baseman Sean Casey to back up Kevin Youkilis. Curt Schilling, Mike Timlin and Josh Beckett were unable to play, and were placed on the disabled list before the season started.

The Red Sox began their season by participating in the third Opening Day game in Major League Baseball history to be played in Japan, where they defeated the Oakland Athletics in the Tokyo Dome.

On May 19th, 2008, cancer survivor Jon Lester threw the 18th no-hitter in team history, beating the Kansas City Royals 7-0. In addition to being his first no-hitter, it was also his first complete game.

The Red Sox continued to play well through the season. The surprise Tampa Bay Rays (formerly the Tampa Bay Devil Rays) took over the top of the division with a sweep over the Red Sox in early July. The Red Sox had lost 7 out of 9 games in a row, and were 5 1/2 games out of first place heading into the last week before the All-Star Break, but the Rays went 0-7 in that week and the Sox took a half-game lead into the break, with the hope of their slugger and DH David Ortiz's return after the break.