Roger Federer will launch his bid for a fifth consecutive US Open title later today, when he plays Argentine Maximo Gonzalez in the first round at Flushing Meadows.
The Swiss, who lost his number one ranking to Rafael Nadal earlier this month, is bidding to win his first grand-slam title of the year, having lost to the Spaniard in the final at both the French Open and Wimbledon.
For the first time in four years, Federer is not the tournament favourite, but the 27-year-old is pinning his hopes on experience.
"I still believe it's an advantage if you know how to win a US Open," the world number two said. "It's a tough tournament to win. Rafa has never been beyond the quarters, so that's definitely the advantage I carry to the other players."
Former champion Marat Safin and 12th seed Richard Gasquet are among the other men in action on day two.
Nadal already booked his place in the second round with a win over Bjorn Phau.
The newly-crowned Olympic champion was made to work for it, but eventually emerged with a 7-6 (7-4) 6-3 7-6 (7-4) win over the German.
Nadal is looking to become the first player since Rod Laver in 1969 to win the French Open, Wimbledon and US Open in the same season.
On the women's side, top seed Ana Ivanovic, looking for her first US Open title, plays Russian Vera Dushevina in round one, while sixth seed Dinara Safina faces American Kristie Haerim Ahn.
Former champion Serena Williams ad her sister Venus also begin their title campaigns on Tuesday.
Fourth seed Serena, beaten by her sister in the Wimbledon final, takes on Kateryna Bondarenko of Ukraine, while seventh-seeded Venus faces Australian Samantha Stosur.
The siblings, who won the gold medal in the doubles event at the Beijing Games earlier this month, are seeded to meet each other in the quarter-finals.
"Obviously we had an unbelievable summer," Venus said. "We are trying to make sure that one of us ends the summer off with a bang."