Wayne was selected by the Indianapolis Colts with the 30th selection in the 2001 NFL Draft. In Wayne's first year, he caught 27 passes for 345 yards with no touchdowns. His yards doubled the next year as he caught 49 passes for 716 yards and four touchdowns.

Wayne broke into the starting lineup for good in the 2003 season, and he caught 68 balls for 838 yards and seven touchdowns. The next season, Wayne caught 77 passes for 1,210 yards and 12 touchdowns during a season in which Colts quarterback Peyton Manning set a then-record by throwing for 49 touchdowns. During the playoffs, Wayne was named the "Wild Card Weekend Offensive Player of the Week" after the Colts beat the Broncos. In 2005 Wayne continued to increase his yearly reception total with 83.

In 2006, Wayne caught 86 balls for a then career high 1,310 yards and 9 touchdowns. As a result, Wayne was selected to his first Pro Bowl. Wayne helped the Colts defeat the Chicago Bears in Super Bowl XLI with a 53-yard touchdown reception in the first quarter.

In 2007, Wayne led the league in receiving yards and was selected to go to the Pro Bowl for the second consecutive year. In 2008, Wayne once again posted another Pro Bowl season with 82 catches for 1145 yards and six touchdowns. In 2009, Wayne caught the winning touchdown pass against the New England Patriots in what is now know as the "4th and 2" game. Wayne was also selected as a starter for the Pro Bowl, but couldn't play due to the Colts playing in the Super Bowl.

In 2010, Wayne was second in the NFL receptions with 111, and third in receiving yards with 1,355. During a season where the Colts heavily relied on Peyton Manning to win games, Wayne again cemented himself as one of the top receivers in the NFL. Wayne was also selected as a starter the Pro Bowl.

On March 13, 2012, the Colts re-signed Wayne to a three-year contract.

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Reggie Wayne