Rex Ryan and his fraternal twin, Rob, were born in Ardmore, Oklahoma, on December 13, 1962, to Doris and Buddy Ryan. When the boys were aged two, their parents amicably divorced. Following the divorce, their mother attended the University of Chicago to earn her doctorate. Rex, Rob, and their older brother Jim moved with her to Toronto, Ontario, Canada, where she secured an administrative position at the University of Toronto.

The Bills opened the 2015 season with a 27-14 win over the Indianapolis Colts. Frustrated by the Bills leading the NFL in penalties heading into their Week 5 game against the Tennessee Titans, Ryan gave the entire team wristbands with the message "Yes sir". These were the only words he wanted his players to use with officials if they were flagged. After being flagged 17 times in Week 4 loss against the New York Giants, the Bills were penalized only seven times in their 14-13 victory over the Titans. The Bills entered their bye week with a 3-4 record after losing in London to the Jacksonville Jaguars. Ryan gave the whole team the week off during the bye, and he himself found a secluded beach to "get away and focus". The Bills came out of their bye week and defeated the Miami Dolphins by a score of 3-17, improving their season record to 4-4. Ryan is now 2-5 all time following a bye week. Ryan returned to MetLife Stadium in Week 10 for a much anticipated Thursday Night Football game against the Jets. The Bills won the game by a score of 22-17, and improved to 5-4 on the season. Ryan faced questions before and after the game about his decision to name IK Enemkpali, who had been released by the Jets in preseason after breaking quarterback Geno Smith's jaw in an altercation, as Buffalo's captain for the game. The Bills were unable to make the playoffs in their first season with Ryan as coach, as they were eliminated in Week 15 with a 35-25 loss to the Washington Redskins on December 20, extending their drought to 16 seasons, the NFL's longest active drought. They finished the season with an 8-8 record.

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The Bills were unable to make the playoffs in their first season with Ryan as coach, as they were eliminated in Week 15 with a 35-25 loss