Buehrle pitched a no-hitter against the Texas Rangers on April 18, 2007, surrendering just one walk to Sammy Sosa who was then picked off at first base.

Two seasons later, Buehrle pitched the 18th perfect game in baseball history, against the Tampa Bay Rays on July 23, 2009.

[4] Buehrle followed this up with an excellent year in 2000, going 8–4 with a 2.28 ERA in 16 starts for the Double-A affiliate Birmingham Barons in Hoover, Alabama, giving up only 17 walks in 119 innings.

[4] Buehrle made his major league debut on July 16, 2000, pitching one inning of relief against the Milwaukee Brewers and allowing a run.

[13] Buehrle was selected to the American League All-Star Team, and was named the starting pitcher after Roy Halladay could not to play due to a broken leg.

[15] Buehrle's streak of 49 consecutive starts of six or more innings ended on August 1, 2005, after he was ejected for hitting Baltimore Orioles outfielder B. J.

The previous time had been on September 29, 1900, when Jack Powell of the St. Louis Cardinals pitched such a game against the Chicago Cubs.

A walk to Sammy Sosa in the fifth inning cost him a perfect game, although he still faced the minimum number of batters, 27, by picking him off at first base two pitches later.

[25] On June 14, 2009, Buehrle hit his first major league home run, off Milwaukee Brewers starting pitcher Braden Looper, becoming the first White Sox pitcher to hit a home run in a game since Jon Garland on June 18, 2006, at Cincinnati.

[30] With the perfect game, Buehrle became the 24th pitcher to throw multiple no-hitters in a career, and the sixth perfect game pitcher who had also thrown another no-hitter, joining Cy Young, Addie Joss, Jim Bunning, Sandy Koufax, and Randy Johnson.

Earlier in the ninth inning, teammate DeWayne Wise, a defensive replacement, made a spectacular catch to rob Gabe Kapler of a home run and preserve the perfect game.

On July 28, his next appearance, Buehrle retired the first 17 batters he faced before finally allowing a baserunner in the sixth inning, setting an MLB record for consecutive outs at 45,[32] which was later broken on August 28, 2014, by Yusmeiro Petit.

[33] Buehrle became only the third pitcher in MLB history (joining Cy Young and Sandy Koufax) to have a no-hitter, a perfect game, and a World Series title with the same team – a feat Buehrle accomplished with the White Sox in 2005 (World Series), 2007 (no-hitter), and 2009 (perfect game).

[35] On April 5, 2010, Buehrle made his eighth career opening day start, setting a franchise record.

[36] In that game he threw 7+1⁄3 shutout innings against the Cleveland Indians and also made an incredible play which involved him flipping the ball to first base between his legs with his glove.

On August 3, 2010, Buehrle won his tenth game of the season against the Detroit Tigers pitching 72⁄3 innings, allowing two earned runs on seven hits and striking out one batter in a 12–2 blowout.

[41] In his debut with the Marlins, Buehrle recorded a loss, giving up two earned runs, in six innings pitched against the Cincinnati Reds.

[7] On November 19, 2012, Buehrle was traded to the Toronto Blue Jays along with Josh Johnson, José Reyes, John Buck and Emilio Bonifacio, in exchange for Jeff Mathis, Adeiny Hechavarria, Henderson Álvarez, Yunel Escobar, Jake Marisnick, Anthony DeSclafani and Justin Nicolino.

[46] Buehrle pitched his first complete game and shutout as a Blue Jay on July 25 against the Houston Astros, and surrendered just two hits and two walks while striking out nine.

He pitched seven innings and yielded only two runs to the Boston Red Sox, and in becoming the majors' first eight-game winner in 2014, gave the Jays a three-game sweep at Fenway Park and a 5–1 road trip.

[55] On June 1, Buehrle became the first starter to reach double digits in wins, taking his 10th game of the season 4–0 over the Kansas City Royals.

[62] Buehrle made what many believed to be his final appearance of the season on October 2, holding the Tampa Bay Rays to four runs over 62⁄3 innings and earning his 15th win.

On October 3, it was reported that Buehrle would attempt to throw the two innings the following day, and would retire afterward, as he did not believe he would be included on the postseason roster.

[63] In the subsequent game, Buehrle was only able to pitch 2⁄3 of an inning, after errors in the field resulted in Tampa Bay scoring eight unearned runs on five hits.

After the game Buehrle, confirmed that he was not named to the Blue Jays' post-season roster, but that he had not yet made a decision about playing the next season.

[65][66] On October 29, Buehrle was announced as a finalist for the pitcher Gold Glove award, along with Sonny Gray and Dallas Keuchel.

He, along with Tony La Russa, bid and won an opportunity to manage the Cardinals for a day at 2010 spring training.

[73] Buehrle's wife Jamie had Orange County Choppers make a surprise motorcycle for him to celebrate his perfect game.

[75] When he was traded to Toronto, he had to leave his pit bull, Slater, behind with his family due to Ontario's ban on the breed.