The two footballing legends have clashed on numerous occasions over the years in some of the biggest matches in the world with both desperate to get one over on their sporting rival.
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There have been El Clasicos that are etched in folklore and Champions League encounters that have dripped in drama as they pushed one another to go to levels never seen before.
But where did it all start? Back in 2008, Manchester United were on course for European glory but Frank Rijkaard's Barcelona stood in his way - step forward, Ronaldo and Messi.
This was one of the best seasons Sir Alex Ferguson had at Old Trafford, led by a jaw-dropping campaign from Ronaldo where he scored 42 times in all competitions - including 31 in the Premier League.
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And all eyes were on the Portuguese superstar, who was just 23 at the time, when United travelled to the Nou Camp to face Barcelona in the semi-finals of the Champions League.
In the space of three minutes, Ronaldo had the chance to give the Red Devils a crucial away goal when Gabriel Milito handled the ball in the box to give United a penalty.
Ronaldo stepped up confidently with the Catalan crowd's whistles reaching deafening levels around the ground - but his side-foot shot went high and wide.
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The forward had his head in his hands after missing a glorious chance to give United a massive early advantage and a chance to quieten the Nou Camp but that did little to shake his confidence.
After the match, Ronaldo said: "I didn't change my style on the penalty, today I didn't score but no problem - I will score in Manchester."
That was the closest United got to Victor Valdes after that flashpoint with Barcelona taking control of the tie, oozing through the mercurial Messi - just 20 at the time.
The little Argentine was at the heart of everything, controlling the game along with Xavi but neither could find a penetrative pass to beat Edwin van der Sar.
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However, Rijkaard was not as impressed and hauled the youngster off after 60 minutes and putting another hot prospect on in the form of Bojan Krkic, whose career did not take off quite as well as Messi and ended up flopping at Stoke.
That decision seemed to stunt Barcelona and they could not muster many better chances until Thierry Henry came on and tried to catch Van der Sar out with a long-range effort.
But ultimately, the match ended 0-0 in Barcelona before Ronaldo and Messi would shake hands a week later at Old Trafford, though the United star did not go through with his promise to get on the scoresheet.
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Instead, it was Paul Scholes that separated the two sides after two legs with a blockbuster shot after 18 minutes while Los Cules had no reply, crashing out of Europe and ending the season without a trophy.
United went on to win the Champions League after their infamous penalty win over Chelsea in Moscow while Rijkaard lost his job and Ronaldinho left the club.
As for Ronaldo and Messi, they would go on to meet many more times and win 12 Ballon d'Ors between them but one looks like they have triumphed over the other.
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Messi added the World Cup to his enormous trophy cabinet in Qatar, ending for many the GOAT debate but in head-to-heads, the Paris Saint-Germain star also comes up trumps.
The two have met each other 34 times in total with Messi being on the winning side 15 times and losing 10, while there have been nine draws between them.
Perhaps for the final time, the pair of footballing icons will face off again - this time in Saudi Arabia with Ronaldo part of a hybrid team of Al-Nassr and Al-Hilal, branded the Riyadh All-Star XI that will face PSG on Thursday.
It will be Ronaldo's first match since moving to the Gulf state, who will also captain the team, after his contract at United was ripped up.
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