Barcelona must reverse an amazing loss of form to win all five of their remaining La Liga games to be assured of retaining their title, starting with a trip to Deportivo la Coruna on Wednesday.
The Catalan giants have taken just one point from their last four La Liga games and lost four of their last five in all competitions having previously enjoyed a 39-game unbeaten run stretching back six months.
Only Barca's superior head-to-head record separates them from their Champions League conquerors Atletico Madrid at the top of the table with Real Madrid lurking just a point further back after a run of seven straight league wins.
All three face tough tests on a Wednesday evening of action that will go a long way to settling the title with the fixture list for all three favourable in the final four games.
Barca are up first as they travel to Galicia in a desperate search to snap their worst run of league defeats in 13 years.
Coach Luis Enrique and key defender Gerard Pique insisted Barca can and will win the league if they play like they did against Valencia on Sunday despite slipping to a 2-1 defeat thanks to a mixture of bad luck, poor finishing and a brilliant goalkeeping display by Diego Alves.
"If there is a team capable of doing it and much more given what they have done, it is this Barca," said Enrique.
"We don't have any margin for error, but I prefer to lose like this than win playing badly," added Pique.
"Football is like this, sometimes it is marvellous, sometimes it is so cruel."
However, Pique's absence at the heart of Barca's defence through suspension will be a huge loss for Enrique with Marc Bartra expected to cover in the absence of Jeremy Mathieu and Thomas Vermaelen.
Atletico face a daunting trip to Athletic Bilbao with the Basques still eyeing Champions League football next season having moved to within six points of fourth-placed Villarreal at the weekend.
A 2-1 victory at San Mames propelled Atletico towards the title two years ago and Diego Simeone's men could be further boosted by the absence of Bilbao's two top scorers this season in Aritz Aduriz and Inaki Williams through injury.
"We have the possibility to play an important game in Bilbao and continue competing in the four games left afterwards," said Simeone when quizzed on Atletico's title chances.
"It will be difficult, but we have to do what the schedule demands of us and that is win, win and win again."
Atletico will be forced into at least one change as captain Gabi is suspended, but Fernando Torres will start alongside 29-goal Antoine Griezmann up front after scoring in four consecutive games for the first time since he was at Liverpool in 2010.
Real will have the advantage of knowing what Barca and Atletico have done when they kick-off in the late game at home to Villarreal.
Zinedine Zidane could afford the luxury of resting the likes of Sergio Ramos, Casemiro and Luka Modric for Saturday's 5-1 rout of Getafe on Saturday with all three expected to return.
The much-criticised Danilo is also expected to start at right-back with Dani Carvajal a major injury doubt.
There are also huge clashes at the bottom of the table with four teams separated by two points in the battle to avoid relegation.
Two of them face each other as Granada host Levante on Thursday looking to open up a gap on the bottom three.
Getafe go in search of their first win in 14 games at Real Sociedad, whilst Sporting Gijon look to take advantage of Sevilla's poor recent run when they host the Europa League semi-finalists at El Molinon.