The Mets selected Humber with the third overall selection in the 2004 MLB draft. During his minor league career, he underwent ulnar collateral ligament reconstruction, before making his MLB debut with the Mets. It took him several years to regain his ability to throw with the same velocity that he had prior to the injury. After being included in a trade to the Twins for Johan Santana, Humber struggled to establish himself. He spent a year with the Royals organization and was briefly a member of the Oakland Athletics organization, before being claimed on waivers by the White Sox in 2011, getting an opportunity to pitch in the White Sox' starting rotation. On April 21, 2012, Humber pitched the 21st perfect game in MLB history, defeating the Seattle Mariners.