World number one Novak Djokovic could face Roger Federer in the US Open semi-finals, while Thursday's draw put defending champion Rafael Nadal in line for a possible last-four clash with Andy Murray.
With the top four men in the world in their appointed places, the men's draw offered little in the way of suspense.
Not so on the women's side, as the lowly 28th seeding of 13-time Grand Slam champion Serena Williams potentially put the American in the path of fourth-seeded Victoria Azarenka of Belarus in the third round.
The men's side promised the renewal of some now-familiar Grand Slam rivalries.
Djokovic boasts a stunning 57-2 record in 2011, and one of the Serbian's two match defeats came against Federer in the French Open semi-finals.
Federer's victory at Roland Garros ended Djokovic's season-opening run of victories at 41 - one shy of equalling John McEnroe's 1984 record of a 42-match unbeaten start to a season.
When Federer beat him at the French, Djokovic had won 43 matches in a row in a streak stretching back to Serbia's 2010 Davis Cup triumph.
Last year Djokovic beat five-time US Open champion Federer in the semi-finals at Flushing Meadows, then lost to Nadal in the final.
In 2011, Djokovic has won all five of his matches against Nadal, all of them in championship matches with the most recent being his Wimbledon triumph.
With that victory Djokovic supplanted the Spaniard as number one in the world.
"To finish the year as number one for me is impossible," Nadal said Thursday after he took part in the draw of the women's field.
"That is not going to happen, because Djokovic is going to finish number one because he deserves to be number one this year.
"For me, it is not something that worries me. What really worries me is to be competitive."
Top-seeded Djokovic is seeded to meet seventh-seeded Gael Monfils of France in the quarter-finals.
Federer could meet eighth-seeded Mardy Fish - the top-ranked American in the men's field - in the quarters.
Potential quarter-final clashes in the bottom half of the draw include second-seeded Nadal against fifth-seeded fellow Spaniard David Ferrer and fourth-seeded Murray of Britain against sixth-seeded Robin Soderling of Sweden.
Djokovic, seeking his first US Open title, opens against a qualifier.
In the third round he could face former top-10 player Nikolay Davydenko of Russia or 32nd-seeded Croatian Ivan Dodig.
Federer, seeking a 17th Grand Slam title but his first since the 2010 Australian Open, could face third-round test against Bernard Tomic.
The Australian teenager became the youngest Wimbledon quarter-finalist since Boris Becker in 1986.
It's a different story on the women's side, where the field is without Kim Clijsters, the two-time reigning champion and winner of the Australian Open in January.
World number one Caroline Wozniacki of Denmark, Azarenka, sixth-seeded French Open champion Li Na of China and seventh-seeded Francesca Schiavone are all in the same half of the draw as Serena Williams, a three-time US Open champion whose world ranking has slipped after health concerns kept her off the court for almost a year.
Williams returned to the tour in June and won two of her first four tournaments, displaying intimidating hardcourt form in lifting trophies at Stanford and Toronto.
Despite her history of success at Flushing Meadows, organizers opted to seed her according to her ranking.
Patrick McEnroe, a former US Davis Cup captain, called Serena Williams "the most dangerous 28th seed in the history of the US Open."
The bottom half of the draw, anchored by second-seeded Russian Vera Zvonareva, also includes Wimbledon champion Petra Kvitova, the fifth seed from the Czech Republic, and third-seeded Russian Maria Sharapova, who could reprise their Wimbledon final in the quarter-finals.
If both stay the course, eighth-seeded Marion Bartoli of France and Zvonareva, runner-up to Clijsters last year, could meet in the quarters.
Venus Williams, a two-time US Open champion, is unseeded in the bottom half of the draw - which means she couldn't face her sister, Serena, until the final.
She could meet Wimbledon semi-finalist Sabine Lisicki of Germany, the 22nd seed, in the second round.