They go into the game with a four-point cushion over their rivals in sixth, although they are only a single point clear of fifth-place Freiburg, which is just another reason why they cannot afford to stumble at the Waldstadion.
They are also only four points behind Bayer Leverkusen, meaning a win would boost their chances of taking an automatic place in the group stage of the Champions League next season.
However, according to striker Teemu Pukki, that is not currently concerning them.
"On the one hand, we would have to hope that Leverkusen slip up," he said. "What is more important is that we do our own homework and play the final five games positively.
"We are now looking from game to game."
Schalke's qualification for Europe cannot be decided on Saturday, and it is unlikely to be determined until late in the season.
They face Hamburg, Borussia Monchengladbach, Stuttgart and Freiburg in their last four matches, all sides still in the hunt for a top-six finish.
"It's good that we have to play against our nearest rivals for a place in Europe," said Pukki on his club's website.
"All of the players in our team are highly motivated and we desperately want to win these matches against direct rivals because not only would that mean three points for us, but that also one of our rivals loses."
Midfielder Jermaine Jones should be fit to face his former club after recovering from an injury he picked up while on international duty for the USA last month.
Roman Neustadter is also back after suspension, giving coach Jens Keller two more options, although striker Klaas-Jan Huntelaar is still a week or so away from full fitness.
Frankfurt are likely to be without their top goalscorer Alexander Meier and captain Pirmin Schwegler, joining Kevin Trapp and Sonny Kittel on the sidelines.
"We have to replace our four best players," said coach Armin Veh. "So we really shouldn't have a chance, but we will give it a go anyway."