Holmes was medalist at the 2005 PGA Tour Qualifying Tournament. He tied for tenth in his first PGA Tour start at the 2006 Sony Open in Hawaii and in February that year he won the FBR Open, making him the fastest golfer to reach $1,000,000 in career earnings on the PGA Tour. It was his fifth tournament as a professional and his fourth on the PGA Tour.
After this victory his form fell away, and this continued in 2007 when he made only 2 top ten finishes and ended the year in 118th place on the money list.
On February 3, 2008, Holmes won the FBR Open for the second Tour win of his career and also captured the tournament title for the second time in three years. Starting the final round with a four shot lead, on the 18th tee he was one shot behind Phil Mickelson. Holmes birdied the 18th to force a play-off and then defeated Mickelson on the first playoff hole (the 18th) by making a six-foot birdie putt after a 359-yard drive. This victory took Holmes to 62nd in the Official World Golf Ranking. In 2008, Holmes reached a career-high 42nd in the OWGR.