Irish trainer Aidan O’Brien will bid to create history in Saturday’s Kentucky Derby at Churchill Downs (23:50 GMT) with the well-fancied Mendelssohn.
No European-based horse has ever won the prestigious race, the first leg of US horse racing’s Triple Crown.
English jockey Ryan Moore has opted to ride the colt rather than take part in the first British Classic of the season, the 2,000 Guineas at Newmarket.
He will fly back to ride Happily for O’Brien in the 1,000 Guineas on Sunday.
The biggest challenge in the Kentucky Derby, which usually attracts a crowd of more than 150,000, is set to come from unbeaten three-year-old Justify.
Trained by Bob Baffert, who guided American Pharoah to wins in the Kentucky Derby, Preakness and Belmont Stakes in 2015, Justify has had three impressive wins this season.
He will bid to end the so-called ‘Curse of Apollo’ – aiming to become the first horse since Apollo in 1882 to win the Kentucky Derby without racing as a two-year-old.
Baffert is bidding for a fifth victory in the race which is known as the Run for the Roses because 554 red roses are awarded to the race winner.
He believes Mendelssohn, who won at the Breeders’ Cup meeting in Del Mar last November and was victorious in the UAE Derby in Meydan in March, has a good chance despite his travel plans being disrupted when his flight had to be diverted from Louisville to Indianapolis because of an issue with travel documents.
“Mendelssohn certainly has the talent to run a big race,” Moore, who faces a 4,000-mile trip back to Newmarket, told Betfair.
“He is a Grade One winner in America, he comes here on the back of a runaway Grade Two win on dirt at Meydan in a track-record time, he has plenty of experience and tactical speed, he has the pedigree, and he has been trained specifically for the race.
“Will that be good enough? I don’t know is the honest answer, and not for one moment do we think this is going to be straightforward, though that is stating the obvious.”
Among the other entries in the 20-strong field is Bolt d’Oro, named after Jamaican Olympic sprint star Usain Bolt.