The Rojiblancos have the unenviable task of trying to dispose of the Kings of the competition who will be looking to take a big step towards landing yet another title in a match where they'll have to do without the talismanic Jude Bellingham, suspended for the first of the two legs in this Round of 16 tie.
History is against the visitors having been beaten in the 2014 and 2016 finals by Los Blancos, as well as being knocked out by them in the 2015 quarter-finals and the 2017 semi-finals, the latter of which was the last time the pair crossed swords in this competition.
Atleti come into the tie in a rich vein of form having only been beaten once in their last 26 fixtures in all competitions.
They've also not lost to Real this season or in any of their last four meetings, with Carlo Ancelotti's side winning only one of the last seven meetings between the teams.
Arguably, Atleti will never have a better chance of breaking their hoodoo and earning the right to face either PSV Eindhoven or Arsenal in the quarter-finals.
Oddly enough, the 12 goals conceded by Real in this season's Champions League is the same as Atleti, as are the 20 goals either side scored in the league stage, evidencing just how well-matched the teams have been to this point.
Bellingham quickly endeared himself to the Santiago Bernabeu faithful last season with 23 goals and 13 assists in his debut LaLiga campaign, but any thoughts that he had gone off the boil in that regard isn't born out by his attacking exploits in 24/25.
Seven goals and six assists is the third-best return in the squad, with, somewhat unsurprisingly, only Kylian Mbappe (17 goals, three assists) and Vinicius Jr. (nine goals, five assists) ahead of him.
Real are perfectly capable of scoring from other areas of the pitch too of course, but there isn't really anyone else in the squad who can replicate Bellingham's lung-bursting and marauding runs back and forth, nor make those brilliant late surges into the box to get on the end of a cross.
Not to mention how the midfielder always wants to get on the ball, take responsibility and get his team moving.
His 138 ball carries in this season's competition is a squad high, whilst the England international is also amongst the best for Real in the Champions League for touches in the opposition box, chances created and attempted dribbles (29).
Of his 22 runs into the attacking third, 21 were into a key area of play, whilst 409 of his 454 passes were completed to give him a superb 90.1% pass accuracy.
An average of nine kilometres covered per UCL game this season is another revealing statistic.
Though Atleti could be said to be a more considered attack-minded team in the main, they need their midfielders to dominate the exchanges in order to move deeper into Real territory and limit the hosts to a counter-attacking game - something which hasn't really worked for Ancelotti's side this season, as their two defeats to Barcelona, for example, will attest.
Although Simeone's men battled to a 4-4 Copa del Rey semi-final draw against the Catalans recently, they were only ever at their best in that game when on the front foot.
When they allowed Barca to play, the Catalans scored. Simple as that. As soon as Atleti pushed forward, pegging Barca back as a result, they were able to dictate the pace and direction of the game and, ultimately, have something to cling onto in the competition.
Players such as Rodrigo De Paul have got to therefore try and get forward at every opportunity to boost Atleti's attacking intent. Twenty five touches in the opposition box in Atleti's entire UCL run thus far is a pathetic return for a player of his evident quality.
Bellingham has recovered 22 balls in this season's Champions League and won 15 tackles, showing that he isn't just a supplementary attacking presence but one who can be relied upon to put in a shift defensively too.
The gap that his absence will create affords Atleti's players the space to get at what has been a brittle Real Madrid defence at times this season, and they have to take advantage.
The one player who Carlo Ancelotti will therefore want kept under lock and key won't be De Paul, but Antoine Griezmann.
In what is expected to be the Frenchman's last season before a move to MLS, his free role has caused untold problems for opponents, both in LaLiga and the Champions League.
In the premier European competition for example, he has double the amount of goals Bellingham has plundered (six to Jude's three), as well as one more assist (three to two).
His 4.4 touches in the opposition box per 90 is also better than Bellingham's 3.4, whilst 2.7 shots per 90 is significant.
Bellingham has often been the conduit for Los Blancos this season but without that ability to knit things together thanks to a high output of 3.1 dribbles per 90, if Griezmann can work the ball well enough in the areas that Bellingham normally likes to patrol, he and his team-mates could find rich pickings.
Whilst you won't find Griezmann driving into the box at pace like his contemporary, what Real have got to get to grips with is the No.7's movement. Drifting into space where there appears to be none has become second nature to him, as has the innate ability to bring colleagues into play thanks to an 84.4% pass accuracy.
Thirteen of his 15 long balls in the competition this season have found their target too, suggesting that if the hosts try to shut him down quickly they're unlikely to dilute his influence on the game.
Putting two men on him surely plays into Atleti's hands too as it opens up what might otherwise be more congested central areas.
The French World Cup winner has already created nine chances in this season's competition, and with Julian Alvarez in particular on fire this season (21 goals in 40 games), Real are likely have a real fight on their hands to keep the Rojiblancos at bay for the full 90 minutes.
It's set to be another mouth-watering Madrid derby and will set things nicely up for the return just a week later.
