Real, who have one game in hand, lead second-placed Barca, champions for the past two years, by three points and, following their recent victory over Bayern Munich, still stand the chance of lifting the Champions League trophy.
Barcelona, on the other hand, look to be on the decline following their European exit and recent lack of league form. Sunday's clash could be Luis Enrique's last hope of turning his team's fortunes around as he prepares to depart the Nou Camp in the summer.
It's a clash that will likely determine the rest of the season and will be sure to provide fireworks.
What time does it start?
Kick-off is Sunday 23 April, 7.45pm (BST) at the Bernabeu.
Where can I watch it?
Sky Sports 1. Coverage starts at 7pm.
It's a big game for...
Luis Enrique. With Barcelona trailing league leaders Real by three points, the Barcelona manager heads into this fixture knowing only a win can reignite his chances of bidding farewell to the club on the back of a league and cup double. The same haul last year was largely seen as a failure. Bowing out of the championship picture now, as the only club of the big three to exit the Champions League, would mean that even winning the Copa del Rey next month couldn't save the 46-year-old from exiting on a low. It's all nothing for Enrique.
Barcelona ran four past their rivals in late 2015? Luis Suarez struck twice at the Bernabeu in a dominant victory that saw Barca move six points clear at the top of La Liga.
Player to watch...
Isco. This could be the game that the midfielder has been waiting for. With Gareth Bale unlikely to feature, despite returning to training on Thursday, Isco has been tipped to start for Zinedine Zidane's side. Gifted and versatile, the player's recent form suggests he is finally poised to achieve something he has yet to manage at the Bernabeu: becoming a firm fixture in the Real starting line-up. His last-minute winner against Sporting Gijon this month showed what he is capable of and suggests Enrique's men should treat him with respect on Sunday.
Past three meetings...
Barcelona 1 Real Madrid 1, La Liga, December 2016
Barcelona 1 Real Madrid 2, La Liga, April 2016
Real Madrid 0 Barcelona 4, La Liga, November 2015
Real Madrid: WWWDWW
Real Madrid to win: 21/20
Barcelona to win: 21/10