After a weekend off due to the postponement of last Saturday's scheduled game between them at the Camp Nou Stadium, FC Barcelona and Real Madrid are both back in action as the Liga Santander moves from its tenth to its 11th round of fixtures in midweek.
Barcelona is in action on Tuesday night as they entertain a Valladolid side that climbed into mid-table at the weekend after a 2-0 win at home to Eibar.
Barca coach Ernesto Valverde has midfielder Sergi Roberto available again after a minor knee issue, although Samuel Umtiti is still sidelined after taking a knock in training a week ago.
Leo Messi, Luis Suarez, and Antoine Griezmann are all likely to start ahead of a midfield of Arthur Melo, Sergio Busquets and Frenkie de Jong, which has begun to gel as a unit in recent weeks.
Atletico Madrid is also in action on Tuesday with Diego Simeone's men looking to follow up their 2-0 home win against Athletic Club Bilbao with three more points away to Deportivo Alaves.
Alvaro Morata looks like a man in form with two goals in the last two games, while Angel Correa should keep his place in the side after a livewire display at the weekend.
Real Madrid has what should be a benign return to action as Zinedine Zidane's side entertain bottom of the table Leganes, who nevertheless claimed their first win of the season on Saturday.
Gareth Bale is still missing for Real Madrid as he struggles to recover from another calf injury and Zidane wants a convincing home win as rumors of Jose Mourinho's return to continue to circle the Santiago Bernabeu.
Real Sociedad could go top if other results go their way and they beat Levante in San Sebastian and all eyes will be on home midfielder Martin Odegaard who has been in excellent form this campaign.
Valencia will be without strikers Rodrigo Moreno (suspended) and Kevin Gameiro with a muscle injury, meaning that Maxi Lopez is set to start in their home game against Sevilla.
Valencia is looking to bounce back from a 3-1 defeat to Osasuna, while Sevilla impressed as they won 2-0 at home to Getafe at the weekend.
Athletic Club Bilbao needs to end a run of five games without a win in which they have scored just two goals when they entertain Espanyol on Wednesday night and coach Gaizka Garitano could make several changes to his side. Espanyol will travel after a morale-boosting first league win under coach Pablo Machin away to Levante at the weekend.
Drama looks to be assured in the Benito Villamarin stadium as third from bottom Betis entertain fourth from bottom Celta Vigo in a game where the stakes are high for both coaches. At the moment both Betis coach Joan Ferrer 'Rubi' and Celta's Fran Escriba are clinging on to their jobs, but the loser on Wednesday looks almost certain to be sacked.
Eibar is also at risk of falling into the bottom three unless they beat in-form Villarreal, who scored four past Alaves last Friday night.
Mallorca entertains Osasuna in a game between two sides who won promotion to the top-flight last season before Getafe entertain league leaders Granada in the last game of the week.
Granada's win over Betis on Sunday took them to the top of the table for the first time since 1973 and a win would see that dream continue until next weekend at the least.