Simeone, often described as playing with a knife between his teeth when he captained Argentina, has brought some of his uncompromising tenacity to Atletico who have lost only once at home since he arrived in the winter break.
La Liga leaders Real, on the other hand, will have their nerves on edge after seeing a 10-point lead over Barcelona cut to four in the space of three weeks. Their latest slipup was a 0-0 draw at home to Valencia on Sunday.
"Perhaps we were a little anxious and rushed when making the final pass," said Real director Emilio Butragueno.
"Wednesday's game will be vital for us to get some breathing space," added the former Real forward known in his playing days as the Vulture. "There is no let up, we have a terrible month in front of us."
While Real have drawn three of their last five league matches, a Lionel Messi-inspired Barca have won nine on the trot and host Getafe on Tuesday (2000).
Real are chasing their first league title since 2008 and have 79 points after 31 games. Barca have 75 and are seeking their fourth straight La Liga crown.
Jose Mourinho's side, on paper, have a tougher run-in, with further trips to play Athletic Bilbao and Barcelona on April 21.
"After drawing against Valencia, we have to win at the Calderon," Real defender Raul Albiol told reporters.
If Real and Barca finish the season level on points the head-to-head results between them would decide the title, as happened when Fabio Capello's Real team won in 2007.
Maintaining a four-point gap helps keep the pressure off the 'clasico' in Barcelona in two weeks time, as Pep Guardiola's side hold a 3-1 advantage from their victory at the Bernabeu in December.
Europa League semi-finalists Atletico, who are seventh, slumped to a 2-0 defeat at Levante on Sunday and are running out of options in their push for a top four finish.
"We have to respect Real because they are the leaders, they are more than 30 points ahead of us, and are one of the best teams in their history," Atletico's Brazilian defender Felipe Luis said.
"We are all very keen to end this run of many years without beating Madrid."