Sergio Ramos vs Luis Suarez
Arguably Spanish football's two most famous pantomime villains, Ramos and Suarez are players whom opposition fans love to hate and there are habitual fireworks when they come up against each other.
In the absence of Messi, Uruguayan forward Suarez will be tasked with providing the finishing touch that his team-mate usually does. Central defender Ramos, heartbeat of this Real team, will be tasked with stopping him.
Gerard Pique vs Karim Benzema
At the other end of the pitch there is a strikingly similar match-up. With Ronaldo gone, French forward Benzema can finally play as a central striker, but has thus far fired mainly blanks.
Pique, who, if Ramos is Mr Real Madrid, is Mr Barcelona, has also made a number of errors that have resulted in his team making a sketchy start to the season. Without the threat of Ronaldo to deal with, the Spaniard will come up against a Benzema determined to make his mark.
Marc-Andre ter Stegen v Thibaut Courtois
With their stalwart central defenders enduring patchy form it is perhaps no surprise that both of these goalkeepers have been busy throughout the opening weeks of the season.
German Ter Stegen has, aside from Messi, arguably been Barca's standout performer, which gives an indication of how overworked he has been.
Courtois, meanwhile, was brought in by Real's club president Florentino Perez to much fanfare this summer after excelling at the World Cup.
Philippe Coutinho vs Gareth Bale
Without Messi and Ronaldo, eyes will be on Barca and Real's club record transfers to make their mark.
Coutinho, who arrived for 142 million pounds in January, took time to adapt to Barca's set up, but is now a key cog in their midfield. In the capital, Bale has yet to show he is the man to fill the Ronaldo void and provide moments of brilliance when his team need it most.