Wood first came to prominence as a 20-year-old rookie, when he recorded 20 strikeouts in a one-hit shutout against the Houston Astros, which some have argued may be the greatest single-game pitching performance in MLB history.

Wood transitioned to a relief pitcher in 2007 due to continued struggles with injuries, ultimately reviving his career as a closer.

[8][9] Two days after being drafted, he started both ends of a doubleheader in the Texas state playoffs, throwing 175 pitches between the two games; the Cubs were outraged.

Wood allowed only two baserunners: Ricky Gutiérrez on an infield single and Craig Biggio, who was hit by a pitch with a count of one ball and two strikes.

The Astros went on to lead the league in on-base percentage, and all of the regulars who were in the lineup, including the four who finished the season batting over .300, went hitless.

Wood underwent successful Tommy John surgery to repair damage to the UCL in his right elbow, and missed the entire 1999 season.

[19] On August 3, 2001, he struck out nine batters and gave up only one run over eight innings to defeat Chan Ho Park and the Los Angeles Dodgers 2-1 [20] to extend the Cubs' lead in National League Central to 3.5 games.

[21] He also walked 100 batters and surrendered 24 home runs, also career highs, but was selected as a National League All-Star and helped lead the Cubs to the playoffs as one half of "Chicago Heat" along with fellow pitcher Mark Prior.

On May 18, 2006, Wood returned to the Cubs' pitching rotation when he started and lost a home game against the Washington Nationals.

The following month, the Cubs announced that Wood had sustained a partially torn rotator cuff, which was likely to keep him from pitching again for the rest of the year.

[22] With his long history of injuries and inability to stay in the starting rotation, Wood accepted the Cubs' offer to return as a relief pitcher in 2007.

[26] Piniella later stated he wanted Wood to receive a "softer landing", or in other words, make his return in a game where the Cubs have a comfortable lead over their opponents.

[18] Wood was generally limited to one inning per outing, not appearing in games on back-to-back days, though he did pitch in both halves of a doubleheader on September 15.

Wood was a major contributor to the Cubs' NL Central Division Championship down the stretch in late September, earning a win and eight holds.

[30] Wood, along with Bob Howry and Carlos Mármol, competed for the role as the Cubs' closer after Ryan Dempster was moved to the starting rotation.

[34] On November 13, 2008, after acquiring closer Kevin Gregg from the Florida Marlins, Cubs general manager Jim Hendry announced that the organization did not plan to re-sign Wood.

[37] Cubs fans showed their appreciation for him by giving him a standing ovation when the Indians played at Wrigley Field on June 19, 2009.

[39] Wood was traded from the Cleveland Indians to the New York Yankees on July 31, 2010, for Andrew Shive, Matt Cusick, and cash.

[40] With the Yankees, he went 2–0 with a 0.69 ERA in 24 games, including 21 straight scoreless appearances, and served as the bridge to Mariano Rivera in the 2010 postseason.

[43] Wood reportedly turned down offers for long-term deals from several other teams worth more money due to his desire to keep his family in Chicago.

[45] Plagued by arm issues and a soaring ERA, Wood retired on May 18, 2012, striking out the only (and therefore final) batter he faced, Dayán Viciedo of the Chicago White Sox.

"[46][47][48] On February 13, 1999, Wood and former high-school teammate Kevin Walker were ticketed for urinating in a parking lot at 1:10 am in Scottsdale, Arizona.