Nowadays, there seems to be a growing sense - or hope, maybe - among the best of the rest on the men's tennis tour that the quartet might be more vulnerable than ever.
Nadal, the 2013 champion at Flushing Meadows, is sidelined by an injured right wrist. Federer is 33 and hasn't won a major championship in more than two years. The No. 1-ranked Djokovic is coming off a triumph at Wimbledon, yes, but he also has a .500 record since. Murray had back surgery and hasn't reached a final anywhere since winning Wimbledon more than a year ago.
If there is going to be a first-time men's major champion, two popular picks are Milos Raonic of Canada and Grigor Dimitrov of Bulgaria. Each is 23; each made his Slam semifinal debut at Wimbledon. While Dimitrov has never won a U.S. Open match, Raonic reached the fourth round the past two years. All six of Raonic's titles came on hard courts, and some opponents consider his serve the sport's best.
ESPN analyst John McEnroe, a four-time winner at the U.S. Open, tips Federer but still has Djokovic down as his favorite - despite an indifferent run of form for the Serbian. McEnroe also believes Murray needs a successful tournament to prove he's back to his best.
"Roger (Federer) looks great and he's probably looked the best out of the top guys this summer. I think Novak (Djokovic) had an incredible run at Wimbledon... and he's sort of, to me, waiting on the Open. I don't think what happened in the summer mattered a lot in terms of his results, so I would still put him as the favorite coming in. And there's the usual cast of characters - (Grigor) Dimitrov and (Milos) Raonic) being the most obvious guys at the top, guys that haven't won, you know they want to sort of put their name in the record books," McEnroe said.
Here are other things to watch at the U.S. Open, running through Sept. 8:
SERENA'S MAJOR CONCERN: Serena Williams could become the first woman in nearly 40 years to win three consecutive U.S. Opens, but she has not been past the fourth round at a major in 2014. After a third-round loss in singles at Wimbledon, Williams made a bizarre exit from doubles, whiffing on practice strokes, having trouble grabbing tennis balls, and quitting after four double-faults in a row.
HARD TIME ON HARD COURTS: Can't list contenders without naming Maria Sharapova, whose five major championships include the 2006 U.S. Open. Or Eugenie Bouchard, the only woman to reach three Grand Slam semifinals in 2014. Neither, though, has looked great on hard courts lately: Since Wimbledon, Sharapova is 4-2, and was pushed to three sets in three of those wins; Bouchard is 1-3.
INJURIES TAKE A TOLL: In addition to Nadal, who is skipping the U.S. Open for the second time in three years, China's Li Na - the No. 3-ranked woman and one of this season's Grand Slam champions - is absent with a knee injury. Del Potro has a wrist injury. Tommy Haas is out after shoulder surgery. There are plenty of players in the draw with various problems, including two-time runner-up Victoria Azarenka, who missed time with a foot injury and more recently had a bad right knee.
ROOF ON THE WAY: After all the rain in recent years, the first significant steps have been taken toward putting a retractable roof on Arthur Ashe Stadium. The project is expected to cost more than $100 million and be ready for the 2016 U.S. Open. It got underway in earnest over the past six months, when steel rods were driven 125 to 180 feet into the ground outside the octagon-shaped arena. What's visible now are concrete pedestals, some covered with plants and one housing a bar, for this year's tournament.