The 26-year-old Swiss has 11 grand slam titles and is hurtling like a hurricane towards Pete Sampras's record of 14.
Another triumph on the hard courts of Flushing Meadows in New York would give Federer three of the four grand slam titles for the second year in a row.
"It is great to be so close," Federer said of Sampras's record. "So close yet so far in a way because slams are not easy to get.
"But I've done a very nice job the last few years picking off as many slams as possible and giving myself a chance over and over again," he told reporters.
"It's one of the big goals for me in my career to not only equal it but break it."
Federer's build-up for the U.S. Open provided an ominous warning to those hoping to achieve the near-impossible task of defeating the world number one in a grand slam.
He won his 50th career title on Sunday to cap stellar preparations to the year's final major.
After beating American James Blake 6-1 6-4 in Cincinnati to win his 14th Masters Series title, he said: "This is the best run I've ever had" during the U.S. Open series.
Rafael Nadal will hope to put an end to Federer's championship run and prove to the world he can win a grand slam tournament outside Paris.
Nadal rules on the slow red clay of Roland Garros, where he remains undefeated in three visits, but a disappointing quarter-final exit at the 2006 Open and
"I am playing good tennis but maybe I have to improve a little bit more," Nadal said recently. "I need to move a little bit better."
Third-ranked Novak Djokovic of Serbia, gritty Russian Nikolay Davydenko or 2003 winner Andy Roddick could stand at the top of the podium should Federer falter.
Roddick will play his second Open under the tutelage of Jimmy Connors, a five-times Open champion who remains the darling of New York's raucous fans.
Despite reaching the final 12 months ago, the American says his game still needs a little tinkering.
"A year later I feel like I made a lot of progress with Jimmy but I feel like we're still building and working towards something," Roddick said.
"It's not like we're together every day. But it's nice to have kind of a mentor and have someone to bounce ideas off, especially someone that knowledgeable about tennis."
Roddick, trying to claim his second major four years after winning his first, said there was no tournament quite like the U.S. Open, which begins on Monday.
"It's probably my favourite tournament as far as the electricity in the air," he said. "I've had a lot of night matches there and it's just something you look forward to.
"You can feel the buzz as soon as you get into the city. There's definitely not another tournament quite like it as far as that goes.
"For tennis to take over a city like New York, it's pretty cool to be a part of every year."