FIFA World Cup Preview: Argentina v Belgium
The Argentina captain has failed to score in his last seven appearances when facing Courtois in Barcelona's meetings with Atletico Madrid, and will be desperate to put the record straight in Brasilia on Saturday.
Messi even missed a penalty against Courtois in the second leg of the Spanish Super Cup in August last year, crashing his effort off the crossbar.
After facing him so many times in club football - Barcelona and Atletico went head-to-head six times during 2013-14 - Courtois believes he is well set to once again get the better of his opponent in the pair's personal dual.
"I know him well from Atletico's games against Barcelona, so it'll be nice to play against him for our countries," the goalkeeper told ESPN.
"Hopefully we can win, but we'll see. The good thing is that I don't have to watch videos of him because I know him so well. But even if you watch videos of him, he's so unpredictable that it's impossible to study him to know what he's going to do.
"As soon as he finds a way to shoot, he will shoot, so the only thing you can do as a goalkeeper is concentrate at all times."
Predictably, Messi has been the driving force behind Argentina's charge to the last eight, scoring four goals as well as laying on the winning strike for Angel di Maria in the dying moments of extra-time in the second round against Switzerland.
Even if his barren run against Courtois continues, Messi is likely to play an influential role, Argentina's talisman has created 18 chances for team-mates thus far, more than any other player in the tournament.
Belgium, fancied as many people's dark horses prior to the finals, are yet to hit top form in Brazil but have developed a useful habit of continuing to win when not quite at their best, and Marc Wilmots' men were pushed all the way by the United States in the last 16 before eventually emerging as 2-1 victors after extra-time.
The two sides last met at the World Cup at the semi-final stage in 1986, when two goals from Diego Maradona saw Argentina through to the final, where they prevailed 3-2 over West Germany to lift the trophy for a second time.
Argentina coach Alejandro Sabella will be forced into a defensive reshuffle to cover for the suspended Marcos Rojo, while Sergio Aguero continues to struggle with the thigh injury that kept him out of the win over Switzerland.
For Belgium, defender Anthony Vanden Borre (cracked fibula) has been ruled out of the remainder of the tournament while Thomas Vermaelen missed the clash with the USA with a hamstring problem and remains doubtful.