In a stunning turnaround in an unfamiliar setting - No. 1 Court instead of Centre Court - the top-seeded Federer blew a third-set match point and, eventually, all of his big lead in a 2-6, 6-7 (5), 7-5, 6-4, 13-11 loss to No. 8 Kevin Anderson on Wednesday in a 4-hour, 14-minute tussle.
Nadal's knees have struggled with the move from clay to grass in recent years but he has breezed through the draw so far and secured another straight-sets win, beating Czech Jiri Vesely 6-3 6-3 6-4.
He won the third set to snap Federer's 34-set winning streak at Wimbledon and Federer was clearly shaken as Anderson dominated the fourth set to drag the 20-times Grand Slam champion into a decider.
In his first Wimbledon semifinal, Anderson will face 2016 runner-up Milos Raonic or ninth-seeded John Isner.
"By the end I thought I did a great job not thinking about what was happening".
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The three-time Wimbledon champion was broken in the opening game of the fourth set, but won the next four games and broke again to clinch victory.
For the first time in three years the Swiss maestro will play a match away from his beloved Centre Court lawn after organisers pencilled him in for a Court One slot. It's just different. I think this gives Anderson a better chance. "That's my problem really".
"It was crucial for him to stay in the match at the beginning of the second set and then it got tougher", said 20-time major victor Federer.
Since he exited Wimbledon at the first-round stage past year, Anderson has enjoyed a solid return, making four finals, including his deep run at the US Open where he finished runner-up to Rafael Nadal.
Kevin Anderson of South Africa reacts after losing a point in his men's quarterfinals match against Switzerland's Roger Federer, at the Wimbledon Tennis Championships, in London, Wednesday July 11, 2018.
The escape energised Anderson and he broke in the next game with a bludgeoning backhand off a weak second serve and then battled back from 0-40 to seal the third with an ace.
Federer was looking fragile and when he netted on the forehand side to hand Anderson a 4-3 lead in the fourth set, the errors were becoming more problematic.
"If you go out there with doubts or unsure what's going to happen, like I maybe did a little bit in that first set, it's not going to go your way".
But the big-serving and obdurate Anderson was undaunted by the situation, staying alive before turning the tide in his favor, preventing Federer from breaking his own record for consecutive sets won at SW19.