He clawed his way from two-sets down to win 2-6, 6-7 (5/7), 7-5, 6-4, 13-11 in four hours and 13 minutes.
"Federer departs Wimbledon at the quarter-final stage and in the slightly unusual surroundings of the No 1 court". You need that mindset against Roger.
It means Nadal is now in his 35th Grand Slam quarterfinal and following previous years of injuries and bad luck at SW19, the Spaniard was pleased to reach the last eight.
The odds are heavily stacked against Kevin Anderson ahead of his Wimbledon quarter-final against defending champion Roger Federer on Wednesday. The South African saved three break points before taking the set 7-5.
Only once before had Federer played more games at a Grand Slam and on that occasion, he prevailed 16-14 in the 2009 Wimbledon final against Andy Roddick.
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After racing through the first set, Djokovic was handed his first code violation for unsportsmanlike conduct after bouncing his racquet into the grass in frustration at squandering three break points in the third game of the second set.
Djokovic wrested back the momentum for good after coming from 0-40 down at 2-2 in the third set to hold serve, and then breaking Nishikori in the next game.
Not only has he yet to drop a set through four matches at the All-England Club this year, but he hasn't had his serve broken, and it wasn't until his last match against Adrian Mannarino that he faced his first break point.
Top seed Federer, 36, has now won 32 consecutive sets at Wimbledon, just two behind his record set from the third round in 2005 to his title triumph in 2006.
Even by Federer's stratospheric standards, the first set was a little absurd.
"Beating Roger Federer at Wimbledon is definitely one I'm going to remember".
The decider went on serve deep into double figures, before Anderson broke in the decisive 23rd game to set up a chance to serve the match - a chance he duly took. Nishikori and John Isner are both through to the quarter-finals for the first time. When I'm doing that, I think I'm a very risky player.