After a stunning 5-2 away win over Inter Milan, the roles will be reversed in Wednesday's return match with Schalke now the heavy favorite to reach the Champions League semifinals and the title holder going in as underdog.
But Inter hasn't given up hope of pulling off the improbable, despite needing to win by four goals to advance.
"I continue to be optimistic. Our goals haven't changed," Inter's Brazilian coach Leonardo said. "Anything is possible.
"That's what I think and the players as well, starting with Eto'o, who knows a thing or two about comebacks, having experienced them first hand. He told us about them and it was really emotional."
Striker Samuel Eto'o was with Barcelona when it overcame a 5-1 deficit against Spanish rival Getafe with a 4-0 win.
"It's fairly difficult to believe in this comeback, but anything is possible in football, even dreams are possible," Eto'o said.
"Inter is a squad made to play a great match and advance. And in the league also, since there are still two months to go," the striker said.
Inter president Massimo Moratti has stood by Leonardo, providing encouragement for the coach into the early hours of the morning following the opening leg.
Inter rallied from a home loss to a German rival to reach the quarterfinals. Inter lost 1-0 at home to Bayern Munich but advanced by winning 3-2 at Munich.
Inter's defense fell apart completely in the opening leg and Leonardo will be happy to have center back Lucio back from suspension.
Another key center back, Walter Samuel, has been included in the squad for the first time since surgery to repair torn ligaments in his right knee in November.
"I don't think he'll play, although it's good that he's on the team," Moratti said.
Cristian Chivu is suspended after getting sent off in the opening leg, but Inter has regained some confidence following a 2-0 win over Chievo Verona on Saturday, bouncing back not only from the opening leg loss to Schalke, but also a 3-0 derby defeat to AC Milan.
Schalke will be missing forward Jefferson Farfan, one of its best players in recent matches, who is also suspended.
But the German side still boasts Raul Gonzalez, the striker with 70 goals in the Champions League.
Schalke seems to have blossomed under new coach Ralf Rangnick, who replaced Felix Magath less than a month ago. It had a 2-0 win over Magath's new team, Wolfsburg, on Saturday in the Bundesliga.
"I will be calm only if we are still three, or even better four goals ahead with five minutes to play," Rangnick said.
Central defender Benedikt Hoewedes said Schalke had to be cautious, especially in defense, not always the team's best department.
"We were underdogs in Milan but we dominated the game. Now, we have to be careful," Hoewedes said.
"Inter will surely do all it can and will throw everything into attack. It's no secret that they have excellent strikers and outstanding attacking qualities. We have to be very alert."