Holders Atletico Madrid will look to gain a healthy advantage in their Copa del Rey last-16 first leg with Segunda B outfit Sant Andreu.
Diego Simone's charges - who defeated city rivals Real Madrid 2-1 after extra time in last season's final - head into the match as overwhelming favourites following a superb start to their Liga campaign.
Atletico have lost just once all season, and sit joint top with reigning champions Barcelona after 15 games.
Their latest success came in a 2-0 triumph at Elche last Saturday, a result that followed a 7-0 demolition of Getafe at Vicente Calderon.
If, as expected, Atletico come through the encounter against their third-tier opponents, a quarter-final tie with Gimnastic or Valencia will await.
La Liga leaders Barcelona have won the Copa del Rey on 26 occasions, more than any other club, and will look to begin their campaign to reclaim the title they last lifted in 2012 by progressing through a seemingly straightforward encounter with second-tier club Cartagena.
The Catalan giants have generally been in superb form this season, but suffered a shock 1-0 defeat at Athletic Bilbao on Sunday - a result that followed a 2-1 setback to Ajax in the UEFA Champions League.
But Gerardo Martino's men should face little difficulty in progressing to the last eight to face the winner of the tie between Girona and Getafe.
Last season's beaten finalists Real Madrid begin their quest for their first success since 2011 against Segunda B club Olimpic Xativa.
Carlo Ancelotti's side have closed the gap at the top of the Liga table to three points following five consecutive league victories, in which Real have notched an impressive 24 goals.
Saturday's 4-0 defeat of Real Valladolid was completed without La Liga top scorer Cristiano Ronaldo, who was absent with a thigh issue, with world-record signing Gareth Bale stepping up in his absence by scoring a hat-trick.
If Real do progress, then a much trickier encounter would await in the quarter-finals, as they are scheduled to play the winner of the all La Liga encounter between Malaga and Osasuna.
The draw produced three top-flight encounters in the last 16, with Villarreal taking on Elche, Celta Vigo meeting Athletic Bilbao, and a showdown between relegation-threatened Real Valladolid and Rayo Vallecano.
Real Betis lie bottom of the Liga standings and new coach Juan Carlos Garrido - who took over from Pepe Mel earlier this week - will be wary of an upset against Lleida Esportiu, while Sevilla and Real Sociedad also face potential banana skins when they meet Racing Santander and Algeciras respectively.
In other fixtures, Levante and Granada play their first legs away at Recreativo Huelva and Alcorcon respectively, while Almeria and Espanyol will look to gain the advantage in their ties with Las Palmas and Real Jaen.