This will be a busy evening for the referee, not least with Uruguay's Atletico Madrid centre-halves Diego Godin and Jose Jimenez up against Portugal's Real Madrid striker Cristiano Ronaldo.
And Messi's Barcelona teammate, Uruguay's Luis Suarez - who bit an opponent at the previous World Cup - has been in top form in Russian Federation while keeping his teeth to himself. That miss, however, has probably fired the 33-year-old to come up with a stronger display in this encounter.
It was thanks to his header that Uruguay beat Italy 1-0 in their decisive group game in Brazil to reach the last 16 of the last World Cup and even though they fell to Colombia in the next round, the memory of the goal lives on.
When it comes to team news, Uruguay is hoping defender Jose Gimenez will be ready for this one after missing the Russian Federation match with a muscle injury. We are going to have to work collectively, but we don't lose sleep over this.
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And Uruguay has identified Ronaldo, with four goals so far at Russian Federation 2018, as the biggest threat to their hopes of a place in the last eight.
"Everybody knows that any team in the world depends on its players, and of course we have one of the best in the world, but you can ask the Uruguay coach the same question about [Luis] Suarez, [Edinson] Cavani - you have great players in every team".
"Nine of the players on the pitch for Portugal are European champions, so that speaks of the quality, and we have been preparing for quite a while". "If Ronaldo plays alone we will lose", said Santos, whose team have gone 17 games without losing - not including penalty shoot-outs - at an global tournament.
If he plays, Portugal's Cristiano Ronaldo (37) will equal Bastian Schweinsteiger (38) as the player with the most appearances at World Cups + European Championships. I've told them they need to be calm. However, they have lost their last three games in the World Cup knockout stages (1 goal scored, 5 conceded). The Portuguese are undefeated in the 2 matches these two teams have played in, with the last match coming in 1972. "That doesn't cross our minds, but if it's boring and we win.", said Uruguay's veteran coach Oscar Washington Tabarez on Friday, looking ever more frail at the age of 71.