Rafael Nadal will try to match his new status as world number one with his first US Open title when the final Grand Slam of the year begins on Monday.
Among those desperate to stop him will be Roger Federer, hoping to bounce back to claim his fifth straight Flushing Meadows crown, and Novak Djokovic, aiming to reproduce his Australian Open form and win his second Grand Slam title of 2008.
In the women's event, the top-ranked Serbians Ana Ivanovic and Jelena Jankovic take on the resurgent Williams sisters and a Russian challenge led by Svetlana Kuznetsova, Elena Dementieva and Dinara Safina.
Nadal, having beaten Federer to win the French Open and Wimbledon, stolen his place at the top of the world rankings and won Olympic gold, is clearly the man to beat.
The Spaniard has never been beyond the quarter-finals in New York but few would bet against him ruining Federer's hopes once more.
"When you are playing well you feel comfortable on all courts," Nadal said.
"In the past when I was playing well, I did well on hard courts, too. I feel good for sure. I won two tournaments in Toronto and the Olympics, and I played semi-finals in Cincinnati."
Federer has won at least one Grand Slam event every year since 2003 and though he said he is feeling less pressure this time, he admitted it would be tough.
"I think I need the [crowd] support a little bit this year," he said.
"[But] I still believe it's an advantage if you know how to win a US Open. It's a tough tournament to win."
Djokovic, runner-up to Federer last year, took his maiden Grand Slam title in Australia in January.
After an early loss at Wimbledon, the Serbian reached the final in Cincinnati and won bronze at the Olympics.
With defending champion Justine Henin having retired and Australian Open champion Maria Sharapova out injured, the women's field looks wide open.
Top seed Ivanovic, who won the French Open in June, comes into the event carrying a thumb injury, while second seed Jankovic, still chasing her first Grand Slam win, has also had to cope with injuries.
"I had a tough year and I've been struggling quite a lot," Jankovic said. "It's tough to expect results but I will try my best."
Wimbledon champion Venus Williams and runner-up Serena Williams could play each other in the last eight, while the Russian challenge is strong again.
Olympic champion Dementieva will take plenty of confidence into her bid for a first Grand Slam title, while former winner Kuznetsova is a big threat.
Safina, the runner-up at the French Open and at the Olympics, believes she too has the game to win.
"Somehow I started to go out there and started to believe I'm a player and I can compete with [the top players]," she said.
"I believe much more in myself and what I'm able to do."