With 10 of the world's Top 100 men out—including world No. 2 Rafael Nadal, the defending champion, and No. 4 Roger Federer—this year's US Open has more of an up-for-grabs feel than ever before.

From rising stars to seasoned veterans, everyone will be eager for the opportunity to seize the title. Here’s a look at five players who could be poised for a major breakthrough.

1 Reilly Opelka

The last player to win a hard-court title before the shutdown, Opelka appeared to be picking up right where he left off with a strong showing at the Western & Southern Open. However, the American was forced to retire from his quarterfinal against Stefanos Tsitsipas due to a knee injury. A few extra days' rest could be beneficial, which could be bad for the seventh seed David Goffin in their first-round match, as well as the rest of the field.

2 Milos Raonic

Speaking of health, that’s long been the concern for one of Canada’s top players. Coming off one of his best tournaments in a couple of years, Raonic showed once again what he’s capable of when he’s able to stay on the court. He has a solid shot at a spot in the second week—and to be playing in the final.

3 John Isner

The summer has been Isner’s time to shine throughout his career, but he hasn’t always been able to parlay that into success at the Open, with only two quarterfinal appearances. He might be in the toughest section of the draw, with top seed Novak Djokovic, but if they meet in the fourth round, the American—who will have fresher legs than usual this tournament—definitely has a fighter’s chance.

4 Andy Murray

It’s been a while since the former world No. 1 has played best-of-five tennis. He faces a tough test in the opening round against Yoshihito Nishioka, but should he get past that, he’s in a fairly favorable section of the draw. As Murray showed last week and over the course of his comeback, he’s up for the battle.

5 Kevin Anderson

Alexander Zverev, the fifth seed, has had many a disappointing Slam in his fairly young career, but recently appeared to be turning the corner. An opening match, though, against two-time major finalist Anderson will be one of his biggest tests. No one has a ton of match play under their belts, which helps level things for Anderson, who has missed a lot of on-court time due to injury. If he’s healthy, the South African can pull off the opening-round upset—and as he’s shown in the past, he knows how to make his way to the championship round of a major.