Cristiano Ronaldo and Co. will be looking to gain revenge for their loss to Diego Simeone's gritty side in the Copa del Rey final in May, while both teams are hoping to get ahead in the frantic race at the top of the La Liga table.
The outspoken Simeone recently proclaimed Real Madrid and Barcelona to be on a completely different plane to every other team in La Liga.
"Madrid and Barcelona play in a different league," Simeone said at an August press conference, as reported by Sky Sports.
"This is a boring championship for the rest of the supporters who can only aspire to be third or fourth," he said.
Such comments would seemingly indicate that Simeone gives Atletico little chance of toppling their archrivals on Saturday night, but few in the Real Madrid camp will consider themselves overwhelming favorites.
Nor will anyone expect Simeone to approach the task with anything other than total commitment. The Argentine will lock horns with new Real manager Carlo Ancelotti, and both will be looking to exploit perceived flaws in their opponent's tactical setup.
This will be a battle not just of individual players, but between two coaches searching for the perfect balance in their starting 11s.
Here are what we expect to be some of the key matchups of an enthralling derby.