Whoever wins will set the final to face either Ralf Nadal or Novak Djokovic.
Isner won the match, and now 14 years on here they both are on Centre Court, competing for a place in the Wimbledon final.
Exhausted Kevin Anderson called for Grand Slam chiefs to introduce a cut-off point for final set marathons after the South African reached the Wimbledon final by winning the second longest ever singles match at a major.
After watching Isner strike a tired forehand wide, Anderson advanced to the Wimbledon final at the 10th time of asking.
It was the longest semi-final ever played at Wimbledon, surpassing the four hours 44 minutes it took Djokovic to beat Juan Martin del Potro in 2013.
South Africa's Kevin Anderson returns against U.S. player John Isner during their men's singles semi-final match on the eleventh day of the 2018 Wimbledon Championships at The All England Lawn Tennis Club in Wimbledon, southwest London, on July 13, 2018.
Paulina Dedaj is a writer/ reporter for Fox News.
He finally broke the 33-year-old American in the 49th game of the decider after coming close in a couple of earlier games and looked impassive as he held his nerve to secure victory.
Anderson and Isner's main strength is their service game, which was pretty apparent given that three sets went to a tie-break.
As it became clear that Isner was due for another endless fifth set, tennis fans were far from delighted.
Isner then shrugged off needing treatment on a blistered serving hand, found time to usher a ladybird to safety before levelling the match in another tiebreak off his 19th ace.
Anderson took a medical timeout after the third set.