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Anderson and Isner combined for 101 aces in a match that lasted six hours and 36 minutes with the South African eventually winning 7-6, 6-7, 6-7, 6-4, 26-24.
Barbora Krejcikova and Katerina Siniakova are one win away from back-to-back Grand Slam titles after advancing to the Wimbledon women's doubles final with a 7-5, 6-4 victory over Alicja Rosolska and Abigail Spears on Friday.
It was that kind of ingeniousness that was needed to break the serve-hold-serve-hold deadlock that went on for nearly three hours in the deciding set alone as Anderson became the first South African man in 97 years to reach the Wimbledon final.
Isner also took part in the longest match - period, no caveats - in tennis history, which, astoundingly, almost doubled the duration of Friday's contest.
Anderson suggested in the aftermath that change was needed at the Grand Slams to stop players from being forced to keep playing for so long.
"You feel like this is a draw for the two of us, but somebody has to win."
Quotable: "I like the level of tennis that I'm playing on right now".
"I can't believe they're going this hard for this long". I have an terrible blister on my right foot.
"John is a great guy and I feel for him", Anderson told the BBC after Friday's match. He had won 34 consecutive sets until midway through his quarterfinal clash against the towering South African Kevin Anderson. The final set alone lasted two hours and 50 minutes. They both serve like demons, and don't return serves particularly well.
Fast facts: Isner leads Anderson 8-3 in head-to-head matchups on the ATP tour.
Isner was the last remaining American in the men's bracket. The match took place over three days.
But he broke right back with some courageous aggressive play, taking this set as well to a tie-break, which witnessed some incredible tennis and some dramatic mini-breaks and nervous double-faults. Djokovic did beat Nadal in the 2011 final at Wimbledon.
At 24-24 Anderson took a tumble but managed to get to his feet and hit a left-handed shot inside the baseline, taking the point for 0-30.
Because Nadal and Djokovic didn't begin playing until after 8 p.m., the retractable roof above the main stadium was shut between the matches and the arena's artificial lights were turned on.
Nadal, the 2008 and 2010 champion, trails Djokovic, the 2011, 2014 and 2015 victor, 26-25 in a rivalry which began at Roland Garros 12 years ago.
Isner had nothing left to give, and his wait for a first Grand Slam final appearance will not come until at least the 42nd attempt, which is the record begrudgingly held by David Ferrer.