Messi will aim to extend his record run of scoring in 11 straight league matches when Barcelona face Valencia.
Barcelona: Days after failing to score in a head-to-head matchup, Lionel Messi and Cristiano Ronaldo will look to rediscover their attacking form when Barcelona visit Valencia and Real Madrid travels to Granada in the Spanish league.
Messi will aim to extend his record run of scoring in 11 straight league matches when Barcelona travels to Mestalla Stadium on Sunday with an 11-point lead in the standings.
Granada welcomes Madrid the day before in the debut of coach Lucas Alcaraz, who replaced Juan Anquela on Wednesday with the team hovering two points above the relegation zone.
Second-place Atletico Madrid hosts fifth-place Real Betis on Sunday with a perfect home record at Vicente Calderon Stadium through 19 games in all competitions.
Barcelona drew 1-1 at Madrid in the first leg of the Copa del Rey semifinals on Wednesday, with neither Messi nor Ronaldo scoring. At least one of the two stars had scored in the previous six clasico matches dating to 2011.
Barcelona squandered several chances to take a commanding lead in the tie. Messi saw his run of scoring in 16 straight starts come to an end, but he did manage to set up Cesc Fabregas for the opener.
Messi leads the Spanish league with 33 goals through 21 rounds after netting four times last weekend against Osasuna.
"We are a little frustrated because we could have scored more goals (against Madrid)," said Barcelona defender Jordi Alba, who is returning to Valencia for the first time since joining Barcelona last offseason.
"I am very excited about going back to Mestalla. Valencia was the club that gave me the opportunity to debut in the first division and to be the player I am today."
Valencia is in seventh place, with four wins in its last five league games under new coach Ernesto Valverde.
Despite playing better recently, Madrid's hopes of defending its league title are close to nonexistent 15 points behind Barcelona in a distant third place.
All the attention in Madrid is on young defender Raphael Varane after his outstanding performance against Barcelona that included a late equalizer.
The 19-year-old Varane has filled in perfectly for the injured Pepe and Sergio Ramos, who will return after completing a five-game suspension for insulting a referee.
"I have no fear," Varane told Spanish sports daily Marca on Friday. "The absences of Pepe and Ramos didn't mean I had more responsibility. I just tried to do the best I can like always."
Besides its new coach, Granada could also see the debut of its winter reinforcements. The Andalusian club signed forward Manuel "Nolito" Agudo from Benfica and attacking midfielder Diego Buonanotte from Malaga on the last two days of the winter transfer window.
Atletico is hoping to recover top-scorer Radamel Falcao in time for the game against Betis, which it already eliminated from the Copa del Rey last month.
Falcao reportedly returned to training on Friday for the first time since hurting his left leg on January 20.
Athletic Bilbao visits Valladolid on Friday to open round 22. Also on Saturday, last-place Deportivo La Coruna plays at Getafe, Osasuna hosts Celta Vigo, and Levante is at Espanyol. On Sunday, Sevilla hosts Rayo Vallecano, Real Zaragoza visits Malaga, and Real Sociedad plays Mallorca.