It was a mixed day for the seeds in Cincinnati, during the round of 16 at the Western and Southern Open on Thursday.
Of the seven remaining seeds, four were knocked out, including third-seeded Rafael Nadal, who fell to 19-year-old Croat Borna Coric.
After taking three sets to defeat Jared Donaldson in the round prior, second seed Stan Wawrinka also lost in straight sets, against a resurgent Grigor Dimitrov.
Kei Nishikori lost both tie-breakers to hand Bernard Tomic the win, and following Gael Monfils' forfeit to Dominic Thiem, Tomas Berdych succumbed to Marin Cilic.
MASTERFUL MURRAY REACHES 600
Following his gold-medal winning run at the Olympic Games in Rio, Andy Murray claimed his 600th career victory on Thursday, comfortably accounting for Kevin Anderson in a 6-3 6-2 triumph.
Despite battling a shoulder complaint in his victory over Juan Monaco, the Scot showed no signs of trouble after securing the break in the eighth game of the first set, going on to win 50 per cent of points returning serve.
There was little fuss in the second set, securing the break in the fifth game to stay on course for a third Cincinnati title.
Milos Raonic - the fourth seed - recovered from back pain to trounce Japanese qualifier, Yuichi Sugita, conceding only ten points in third set to win 6-1 3-6 6-1.
CORIC CHILLS NADAL'S HOPES
In the biggest shock of the day, Coric only needed an hour, 12 minutes to dispatch Spaniard Rafael Nadal, in a 6-1 6-3 win.
Similarly to his victory over Nick Kyrgios, the world number 49 took full advantage of Nadal's faltering serve, winning 37 per cent of points returning, while the world number five served four double faults in the opening set.
Coric now holds a rare advantage in the head-to-head record over Nadal, albeit after three matches, following the latter's win in four sets at Flushing Meadows last year.
Meanwhile, Grigor Dimitrov looks to be bouncing back from his opening-round loss to Marin Cilic in Rio, in a 6-4 6-4 over Wawrinka.
OLYMPIC CHAMPION MURRAY THE HEADLINE ACT
Andy Murray's clash with Bernard Tomic looks to be the pick of the quarter-final schedule on Friday, after Australian coolly claimed a 7-6 (7-1) 7-6 (7-5) over Nishikori. It will be an all-Croatian quarter-final when Cilic faces Coric, while Raonic will be up against Dominic Thiem. In the other tie, Dimitrov is set to take on Steve Johnson after he defeated Jo-Wilfried Tsonga.