Barcelona, Real Madrid and holders Atletico Madrid all get their Copa del Rey campaigns under way this weekend as they travel to lower league opposition for fourth round ties.
La Liga leaders Barca are first up on Friday night as they travel to Segunda B Division opponents Cartagena in the first leg of their matchup.
After suffering two consecutive defeats to Ajax and Athletic Bilbao to end his unbeaten record since taking charge of the Catalans, Barca boss Gerardo Martino is expected to name a strong side to avoid another embarrassment.
Those defeats have brought an unusual amount of criticism the way of the Barcelona staff and squad for a side that remains top of La Liga, albeit only on goal difference from Atletico, and has already secured its place in the last 16 of the Champions League.
However, defender Gerard Pique has said he is not fazed by the criticism as long as it remains constructive.
"The Cup is what we are faced with now and it is a good opportunity to put in a good performance that will give us confidence," he said.
"We are prepared for all this, but I like the criticism to be constructive. It is another thing to lack respect, like what happened the other day when they asked (Andres) Iniesta if we are training well.
"Obviously we accept the criticism. I don't consider it a lack of respect that they say there ought to be changes in the squad, but I have a lot of confidence and faith in the team and I am sure the results and titles will come."
Atletico, who could meet neighbours Real Madrid in the semi-finals should both sides progress to the last four, also begin the defence of their title at third tier opposition as they travel to Sant Andreu on Saturday.
Diego Simeone's men enjoyed an unbeaten on their path to a 10th Cup success in May, which culminated with their first win in 14 years over Real at the Santiago Bernabeu.
Given Los Rojiblancos success in Cup competitions under the Argentine, Simeone is expected to take the competition seriously despite his side's on-going challenge in La Liga and the Champions League.
Free-scoring Real Madrid are also in first leg action on Saturday as they visit Olimpic Xativa.
The Valencian side lie just five points above Madrid's C team in the overall Segunda B standings and face an uphill task trying to stop a Madrid attack that has scored 30 goals in their last seven games.
Cristiano Ronaldo is suspended for Los Blancos after he was sent-off in last season's final, but Gareth Bale could get his first taste of Copa del Rey action after bagging his maiden hat-trick in Spanish football during last weekend's 4-0 thrashing of Valladolid.
Fixtures (all times GMT)
Lleida v Real Betis (1100)
Villarreal v Elche (1500)
Algeciras v Real Sociedad (1700)
Racing Santander v Sevilla (1900)
Valladolid v Rayo Vallecano (2100)
Cartagena v Barcelona (2100)
Sant Andreu v Atletico Madrid (1500)
Girona v Getafe (1700)
Celta Vigo v Athletic Bilbao (1900)
Olimpic Xativa v Real Madrid (2100)
Recreativo Huelva v Levante (2100)
Alcorcon v Granada (1100)
Gimnastic v Valencia (1600)
Las Palmas v Almeria (1600)
Real Jaen v Espanyol (1800)
Malaga v Osasuna (2000)