Schalke, who cruised past Steaua Bucharest 3-0 on Wednesday night, host Bayern Munich, who defeated CSKA Moscow by the same scoreline on Tuesday, in an intriguing encounter at the Arena AufSchalke.
With the Royal Blues winning their last three games without conceding a goal, Bayern's 30-game unbeaten streak is at risk in Gelsenkirchen while Schalke have no intention of interrupting their recovery after a difficult start to the season.
"We know we're underdogs, but we've got realistic chances of winning or getting a point," said midfielder Julian Draxler.
A glimpse at the statistics does little to support the Germany international's feeling, with Bayern winning their last five games against Schalke - all since goalkeeper Manuel Neuer switched clubs.
"Bayern won everything going last year so it's not going to be easy," said Schalke coach Jens Keller.
"But we've kept three clean sheets in a row and I'm particularly pleased about that."
A win might not be enough to take Bayern to the top of the Bundesliga, though, since Borussia Dortmund, who lost their Champions League opener to Napoli on Wednesday night, can extend their lead at the top with a sixth straight win at Nurnberg.
Bayer Leverkusen could also steal a march on Pep Guardiola's men with victory at Mainz while Hannover could draw level on points by picking up their fourth win of the season against Augsburg, who have won their last three games in a row, setting a new club record in the process.
The weekend's first game sees Eintracht Braunschweig head to Borussia Monchengladbach on Friday night, still searching for their first win of the season.
Saturday also sees the northern derby between Hamburg and Werder Bremen in the first game since Hamburg parted company with coach Thorsten Fink.
Wolfsburg host Hoffenheim while Germany's Europa League representatives Freiburg and Eintracht Frankfurt are in action on Sunday against Hertha Berlin and at Stuttgart respectively.