John Isner retired from his second-round match Wednesday at Wimbledon because of a knee injury and giant-killer Steve Darcis was unable to take the court for his match because of a shoulder problem.

Also, on the women's side, second-seeded Victoria Azarenka also pulled out prior to her second-round match with an undisclosed injury.

Isner hurt his left knee early in his match against Adrian Mannarino, took an injury timeout and called it quits after two games.

The 18th-seeded American, of course, is best known at the All England Club for playing the longest match in tennis history three years ago with a five-set marathon in the first round against Nicolas Mahut. The 11-hour, 5-minute epic took three days to complete because of rain and darkness, ending with a 70-68 score in the final set.

Darcis, meanwhile, withdrew before his scheduled second-rounder against Lukas Kubot of Poland. The Belgian pulled off one of the biggest upsets in Grand Slam history on Monday with a three-set shocker over two-time Wimbledon champ Rafael Nadal.

"Had to withdrawn after a win like this!?THE most difficult thing i had to do!!!#triedeverythingtoplaybutdidntwork!!!!" Darcis wrote on Twitter.

Azarenka was slated to take on Flavia Pennetta in the second round, but she was clearly hobbled during her first-round win over Portugal's Maria Joao Koehler. Azarenka did a split behind the baseline during the match and appeared to injure her right knee, which required treatment on three occasions as she completed a 6-1, 6-2 triumph.

The reigning Australian Open champ apparently tried to warm up on Wednesday morning before the match, but was unable to play, giving Pennetta a walkover into the third round.

Men's 10th seed Marin Cilic also pulled out on Day 3. The big Croat was scheduled to meet Frenchman Kenny De Schepper, but decided against playing due to a left knee injury.