With Barca currently top of La Liga and eight points ahead of their rivals, Real need victory in El Clasico to have any hope of catching them.
Lose at the Bernabeu and Los Blancos will fall 11 points behind and all but rule themselves out of the title race.
Victory, on the other hand, will close the gap to five points and blow the title race wide open - even for second-placed Valencia and third-placed Atletico Madrid.
Much will depend on whether Real can control Lionel Messi, who is in red-hot goalscoring form at the moment.
Messi's 14 goals in La Liga means he's top goalscorer by some distance and 10 ahead of his nemesis, Cristiano Ronaldo.
Stopping the Argentine is a huge ask of Real's defence, but they need only ask Xabi Alonso for some advice about how to do just that.
Alonso, who retired earlier this year, spent five years in the Spanish capital and played against Messi more times then he cares to count.
And in a recent interview with Ecos del Balne, he explained the tactic ex-Real boss Jose Mourinho used to use to "control" Messi in El Clasicos.
Take it away, Xabi.
"Messi has done a lot of damage to me," admitted Alonso, per the Mirror. "Me, Mourinho and Sergio Ramos talked about him a lot.
"We only started to control Messi when I was marking him. We sacrificed positions for me to mark him, but once we controlled Messi the matches were even."
Messi is renowned for dropping deep to pick up possession, so whenever Real faced Barcelona, Mourinho made the decision to have Alonso man-mark him.
It's a smart move that clearly does work, as evidenced by Pablo Maffeo's masterclass against Messi during Girona 0-3 Barcelona in September.
With so much at stake, Zinedine Zidine might be wise to head Alonso's advice and instruct Casemiro to track Messi.