Roger Federer was stunned in the Miami Open second round, while Alexander Zverev and Nick Kyrgios had contrasting wins on Saturday.
Defending champion Federer was downed by Australian qualifier Thanasi Kokkinakis in three sets in a defeat which will see him drop from world number one.
Zverev also played a final-set tie-break, but the German managed to edge through, while Kyrgios marked his return with a comfortable win.
A three-time champion, Federer went down to Kokkinakis 3-6 6-3 7-6 (7-4) after two hours, 21 minutes.
The Swiss 20-time grand slam winner lost just seven points on serve in the final set, but he was edged by the world number 175.
Federer, who later announced he would again skip the clay-court season, will lose his number one ranking after the early exit.
ZVEREV BATTLES THROUGH
Zverev, the fourth seed, overcame fellow young gun Daniil Medvedev 6-4 1-6 7-6 (7-5).
The German's win marked his third in as many meetings with Medvedev, who took a set off the 20-year-old for the first time.
Zverev will next face veteran David Ferrer after the Spanish 28th seed cruised past Evgeny Donskoy 6-2 6-2.
KYRGIOS CRUISES ON RETURN
Returning from an elbow injury, Kyrgios had no troubles crushing Dusan Lajovic 6-4 6-1.
The Australian's win came on a good day for the seeds, with 12 of the 16 in action advancing.
Adrian Mannarino, Kyle Edmund and Damir Dzumhur joined Federer as the seeds to fall.