The top two seeds were stunned in Friday's quarterfinal action, while Venus Williams pressed on into the semifinals at the WTA's $2.168 million Western & Southern Open.
The second-seeded former world No. 1 Serena Williams was ousted by fifth- seeded left-hander Angelique Kerber, 6-4, 6-4. The German pulled off the upset in 76 minutes by breaking the American's powerful serve twice while holding her serve throughout on Day 5.
The rising Kerber now has a remarkable seven wins against top-10 women this year.
Serena was riding a torrid 19-match winning streak since being stunned in the first round at the French Open in June. The 14-time Grand Slam champ was seeking a fourth straight tournament title after posting big wins at Wimbledon, Stanford and the London Olympic Games.
Top-seeded Pole Agnieszka Radwanska was bounced in short order by No. 9 seed, Li Na of China, 6-1, 6-1, in just 70 minutes.
Li advanced to the quarterfinals earlier on Friday, when she leveled Swedish qualifier Johanna Larsson, 6-2, 6-2, making up a match that was postponed due to rain Thursday night.
Meanwhile, the wild card Venus upended third-seeded U.S. Open champion Sam Stosur, 6-2, 6-7 (2-7), 6-4 on the hardcourts at the Lindner Family Tennis Center. The former No. 1 American advanced in 2 hours, 34 minutes despite piling up nine double faults.
The 32-year-old seven-time Grand Slam singles champion Venus, who's been slowed mightily by an autoimmune disease over the last couple of seasons, will appear in her first semifinal in almost two years, or since the 2010 U.S. Open.
Czech Petra Kvitova, who topped Li in the Montreal final on Monday, also advanced to the semifinals after beating Russian Anastasia Pavlyuchenkova 6-3, 7-6 (7-4).
The third round was completed on Friday when the 17th-seeded Pavlyuchenkova upset sixth-seeded former top-ranked Danish star Caroline Wozniacki 6-4, 6-4, after the match was suspended Thursday night.