On January 17, 2011, a year and a half after Jobs returned to work following the liver transplant, Apple announced that he had been granted a medical leave of absence. Jobs announced his leave in a letter to employees, stating his decision was made "so he could focus on his health". As it did at the time of his 2009 medical leave, Apple announced that Tim Cook would run day-to-day operations and that Jobs would continue to be involved in major strategic decisions at the company. While on leave, Jobs appeared at the iPad 2 launch event on March 2, the WWDC keynote introducing iCloud on June 6, and before the Cupertino City Council on June 7.

On August 24, 2011, Jobs announced his resignation as Apple's CEO, writing to the board, "I have always said if there ever came a day when I could no longer meet my duties and expectations as Apple's CEO, I would be the first to let you know. Unfortunately, that day has come." Jobs became chairman of the board and named Tim Cook as his successor as CEO. Jobs continued to work for Apple until the day before his death six weeks later.