The Special One has been here before with Chelsea. In 2005 and 2007 under his management, the Blues reached the semi-finals of the Champions League, only to be knocked out by Liverpool.
However, not only are Atletico unbeaten in front of their own supporters in La Liga this season, which has helped them to top the standings with four matches left to play, no English club has ever won from their trips to the Calderon.
Any positive result that the West Londoners are to achieve will have to be done so without the services of right-back Branislav Ivanovic, who is suspended. Consequently, Mourinho may recall the experienced Ashley Cole, with Cesar Azpilicueta switching flanks to cover Ivanovic's absence.
As well Ivanovic, Eden Hazard could also miss out. The Belgian playmaker has not played for two weeks because of a calf complaint, with the match in the Spanish capital potentially coming too soon.
Elsewhere, Nemanja Matic and Mohamed Salah are cup-tied, but goalkeeper Petr Cech should recover from illness to feature between the posts.
Meanwhile, Atletico's major selection dilemma heavily centres around the visitors. Thibaut Courtois is in his third season on loan with Los Rojiblancos from Chelsea, but despite having a foot in both camps, UEFA have insisted that there is no clause to prevent the 21-year-old from keeping goal for the home side.
That aside, Diego Simeone has been boosted by the news that Turkish midfielder Arda Turan is fit to feature along with leading goalscorer Diego Costa, who has been heavily linked with a summer switch to Stamford Bridge.
Atletico may have shown positive home form this term, but it's worth noting that Chelsea have not lost in Spain since a 1-0 defeat to Real Betis back in 2005 - a run that dates back seven Iberian encounters.
Possible starting lineups
Atletico: Courtois; Juanfran, Miranda, Godin, Filipe; Suarez, Gabi, Koke, Turan; Villa; Costa
Chelsea: Cech; Azpilicueta, Cahill, Terry, Cole; Lampard, Ramires; Oscar, Willian, Schurrle; Eto'o
Tag : Champions League