Stan Wawrinka and Roger Federer, the respective winner and runner-up at least year's ATP Monte Carlo Masters, were both dumped out in the third round on Thursday.
Federer, a four-time finalist at this ATP 1000 clay-court event, was beaten 6-4 7-6 (7-5) by world number 18 Gael Monfils.
There was little sign of the surprise to come when Federer took a 3-1 lead in the opening set, but his opponent fought back strongly to get himself in front.
The second set proved a tight affair, with no breaks of serve, and in the tie-break Monfils once again showed his battling qualities, recovering from 5-3 down to stun his opponent.
Meanwhile, Wawrinka's defence was ended by Grigor Dimitrov.
The Bulgarian dominated proceedings from start to finish, claiming five breaks of serve in a 6-1 6-2 success which took less than an hour, as he booked a quarter-final meeting with Monfils.
Unlike Federer and Wawrinka, world number one Novak Djokovic had little trouble in his third-round match as he dispatched Andreas Haider-Maurer 6-4 6-0 with a minimum of fuss.
Djokovic will now meet Marin Cilic, who prevailed 6-3 7-6 (7-5) over Jo-Wilfried Tsonga.
Rafael Nadal, whose defeat to Djokovic in the 2013 final ended a run of eight consecutive titles at this tournament, had to work a little harder in seeing off John Isner 7-6 (8-6) 4-6 6-3.
After edging the first-set tie-break, Nadal dropped his serve for the first time in game nine of the second, and Isner held to force a decider.
Nadal finally made inroads on the Isner serve in game four of the third, before going on to take victory and set up a quarter-final with compatriot David Ferrer, who overcame Gilles Simon 6-2 6-7 (3-7) 6-1.
Milos Raonic is also through to the last eight, after he overcame Tommy Robredo 6-3 3-6 6-3.
The fourth seed will take on Tomas Berdych, after the Czech's 7-6 (9-7) 6-4 victory against Roberto Bautista Agut.