The Madrid derby usually induces pessimism in the red and white half of the Spanish capital with Atletico last managing to beat their city rivals with a 3-1 away win in 1999.
They have suffered nine defeats to Real in their last 10 league meetings at the Calderon, but the man who has engineered this year's impressive campaign is keen to change history.
But with Real focused on overturning a 4-1 Champions League semi-final first-leg deficit against Borussia Dortmund - not to mention reports that Cristiano Ronaldo will sit out the Liga clash in hopes of being fit to face the German side - this could be Atleti's chance to get one over their rivals.
"You have to go back many years before you find a time when we were competing for league positions as well as for the game," Argentine Simeone told a news conference on Wednesday.
"We have played them in many different circumstances and it hasn't gone well. Saturday is a new opportunity and you have to make the most of it."
The game also acts as a prelude for the King's Cup final when the two sides will clash again, this time at the Bernabeu on May 17.
Atletico were boosted when striker Diego Costa's yellow card from last weekend was overturned on appeal on Wednesday, meaning their pugnacious striker is available to play.
Atletico are close to securing a berth in the Champions League group stage, but the battle for the fourth spot, which requires entry through qualifying, is set to run to the end of the season.
Surprise-package Real Sociedad occupy fourth place, 13 points behind Atletico, but two ahead of fifth-placed Valencia who visit Sociedad's Anoeta stadium on Sunday.
Atletico enforcer Gabi Fernandez realises whoever they come up against in the Real Madrid squad, they will be strong.
“It’s a very long time since we beat them, at the same time, it’s also been a long time since we’ve come up against them in a situation like this,” reflected Gabi to reporters.
“We can go level on points with Real Madrid. We also play them soon in the Copa del Rey Final.
“We are at a very high level and we must seize the opportunities given. We all dreamed of reaching the end of the season level with Madrid.
“We’re waiting to play Real Madrid. Whichever player plays, we want to win the game. Like for us, second place for them is also important. Nobody expected the result yesterday, but they have class players and know how to overcome it.
“The team has been working hard to be in the situation we are in, the truth is the opponent generates a lot of interest because of the type of the game this is.
“For us it is a special game and we really want to win.
“Any Real Madrid player has the ability to win the game. They have players like Ozil and Cristiano who can make the difference.
“If they do not come and Mourinho believes he doesn’t have to play them, that’s good for us, but it is clear that we will come up against a very strong team.”
Atleti also know that a win over Madrid could also send the title to Barcelona, should the Catalans win their earlier game at Athletic Bilbao.
“We just want to beat Madrid. If Barcelona are crowned League champion this weekend it’s because they have earned it.
“We will think about our game and our goal is to get as high as possible and we have the opportunity to advance a position.”
MATCH FACTS (Courtesy of Opta)
Atletico are winless in 22 league meetings with Real Madrid (6D 16L), the longest run without a victory by any side in any Spanish top-flight derby.
Real Madrid have won their last five trips to the Calderon in La Liga, their best ever away run against Atleti in the league.
Real Madrid are the only team Atletico have not beaten in the league since their promotion in 2002.
Atletico have conceded at least one goal in each of their last 16 home derbies with Real (2.3 goals per game on average).
The Whites have scored their first goal in the 14th minute of the game on average in their 10 trips to the Calderon since Atletico last won promotion.
Only in 1991/92 (16) have Atletico won more home games than they have in 2012/13 so far (14).
Gonzalo Higuain scored his first La Liga goal at the Calderon in February 2007 (1-1), in the only derby that Fernando Torres netted in for Atletico.
Since that day, only Lionel Messi (202) and Cristiano Ronaldo (143) have scored more La Liga goals than Higuain (104).
Atletico and Real Madrid have been given a joint-high eight penalties this term.
Falcao has become the first player since Diego Forlan in 2008/09 (32) to reach 25 league goals in a single campaign for Atletico.
Cristiano Ronaldo has scored six of Real’s last 10 derby goals, with five coming from dead ball situations (three penalties, two direct free kicks).
Only Atletico (25) have conceded fewer league goals than Real (30) so far this term.
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WEEKEND MATCHCASTS (All kick-off times BST)