It was an all-or-nothing match last time the two sides met at the Camp Nou in the final game of last season with a draw giving the visitors the title.
Now while the stakes are not as high, a negative result could have a major impact on the future of Luis Enrique.
It is a perfect time for Diego Simeone's Atletico side to face Barca who have failed to convince this season and are embroiled in a supposed rift between Luis Enrique and Messi.
The pair are believed to have almost come to blows during a training session last Friday and then had a heated argument after Sunday's La Liga defeat by Real Sociedad.
That result left champions Atletico level with Barcelona on 38 points, one less than leaders Real Madrid who also have a game in hand of their two title rivals.
While Barcelona have hit the headlines for the wrong reasons, Simeone has gone about the business of adapting new players to his system with quiet efficiency.
In the wake of the departure of key players such as striker Diego Costa, they started the season slowly but have picked up the pace and began the New Year with a victory over Levante in La Liga followed by a win against Real Madrid in the first leg of their King's Cup last 16 tie.
"I don't understand this game without the word competition," Simeone said. "In order to compete against opposition you need to compete together. The team is working very hard.
"In order to have success in three competitions you need to have a group. The team is competitive and we will take on the opposition in whichever competition."
Returning hero Fernando Torres has been the centre of attention since arriving back at the Calderon in the January transfer window but he had a quiet game against Real.
Simeone urged patience with the Spain striker, who left Atletico for Liverpool and then moved to Chelsea and Milan.
"He offers drive and energy," said Simeone. "He is strong and fast but needs more time to create an understanding with his team mates."
Real Madrid finished 2014 with a Spanish record 22 consecutive victories but after a La Liga defeat by Valencia and the loss to Atletico they will need to get back on track against Espanyol on Saturday.
(Editing by Martyn Herman)
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