Fighting it out for the right to tackle Atalanta BC in the last 16, the sides are separated by six points in the second-tier standings, following a fast start from the Nerazzurri.
Match preview
With a record of four wins and two draws in Serie B this season, Pisa sit top of the table by two points from second-placed Spezia, as they aim to end a three-decade wait for promotion to Italy's top flight.
Sacked by relegation-bound Salernitana in February, Pippo Inzaghi was back in the dugout after a few months of reflection, taking up the challenge of leading the Nerazzurri back into Serie A.
Saturday's 2-1 home win over close challengers Brescia leaves his side on course to reach the promised land, but achieving that feat will be more of a marathon than a sprint.
Marco Tramoni has now scored in three consecutive matches, and the France-born forward was also on target during Pisa's victory in the first round of this season's Coppa Italia.
He opened the scoring against Frosinone in a 3-0 away win that put the Tuscan club into this week's second round, and another win on Wednesday would send Inzaghi back to former club Atalanta in the last 16.
However, Cesena stand in their way, having reached this stage of the Coppa by a somewhat tougher route.
Michele Mignani's men were first required to see off Padova in the preliminary round, before being handed a first-round tie away to top-flight opposition.
Stunning Hellas Verona at Stadio Bentegodi, they pulled off a 2-1 victory over the Serie A side, with Cristian Shpendi scoring what turned out to be the match-winner early in the second half.
Since then, the Bianconeri have won, drawn and lost two games to sit 10th in the early Serie B standings, most recently holding Palermo goalless last weekend.
After a game in which four goals were ruled out for offside - three for Cesena, and Shpendi on each occasion - Mignani will hope for better luck at Arena Garibaldi.
Pisa Coppa Italia form:
W
Pisa form (all competitions):
D
W
D
W
W
W
Cesena Coppa Italia form:
W
W
Cesena form (all competitions):
W
L
W
L
D
D
Team News
Cesena are set to make changes to the team that started against Palermo on Saturday, so forwards such as Sydney van Hooijdonk and Mirko Antonucci could be in line for promotion to the first XI.
Three-goal top scorer Cristian Shpendi and Sierra Leone striker Augustus Kargbo are also in contention for places in the final third.
One man not available to Michele Mignani, though, is rising star Tommaso Berti, who was recently ruled out for several weeks by a leg injury.
Meanwhile, Pippo Inzaghi will be without winger Emanuel Vignato, who intermittently impressed when in Serie A with Bologna.
Pisa could also freshen up their side on Wednesday, but top scorer Nicholas Bonfanti usually leads the hosts' attack, supported from behind by Stefano Moreo and Marco Tramoni.
Pisa possible starting lineup:
Semper; Canestrelli, Caracciolo, G. Bonfanti; Piccinini, Abildgaard, Hojholt, Angori; Mlakar, Tramoni; N. Bonfanti
Cesena possible starting lineup:
Pisseri; Curto, Prestia, Mangraviti; Ceesay, Mendicino, Calo, Bastoni, Donnarumma; Antonucci, Shpendi
We say: Pisa 3-1 Cesena
Pisa seem to be heading in the right direction under Pippo Inzaghi, and they are not only top of Serie B at the moment but are also the second tier's leading goalscorers.