The five-year-old gelding came desperately close to winning America's richest horse race last year, only to be run down by Drosselmeyer in the shadows of the post.
Twelve months later, Game On Dude is fitter, stronger and the overwhelming favourite to emulate his sire, the 1998 classic champion Awesome Again, by winning the one-and-a-quarter mile test of speed and stamina.
Game On Dude has won four of the six races he has contested since last year's Classic but he is not the only one trying to make the most of his second chance.
His Hall of Fame trainer Bob Baffert is also making every second count after he survived a brush with death in March when he took the horse to the United Arab Emirates for the Dubai World Cup.
Unaware that anything was wrong with him, the 59-year-old suffered a heart attack and was convinced he was going to die.
He was rushed to hospital and had three stents inserted in two arteries. It was touch and go and the experience instantly changed Baffert's outlook on life.
Baffert has won three Kentucky Derbies and most major races on the American calendar but is still chasing his first Classic winner, not that it worries him. More than anything else, his close shave gave him a fresh perspective on life and racing.
"After the heart attack, it changed my way of thinking," Baffert said. "I don't take it for granted. I got a second chance."
Last year, Game On Dude was ridden by Chantal Sutherland, who was bidding to become the first female jockey to win the prestigious race.
This weekend, Rafael Bejarano will be in the saddle after Baffert made the decision to replace Sutherland with his top stable jockey.
"Rafael is our main rider and we wanted to have our No. 1 rider on our No. 1 horses," Baffert said. "With the big fall races coming up, we just felt comfortable having Rafael on Game On Dude.
"It was difficult for me when I told Chantal about the decision. It's been a fun ride and we made history together, but we just felt it was time to make the change.
"He (Bejarano) is a real team player. Even when he wasn't riding him, he was willing to help out. How about that? You've got the leading rider around here and he's willing to put his ego aside and be part of our team."