Italy legend Alessandro Nesta will take the underdogs to the cauldron that is Marassi in hope of causing another upset in this year's competition.
Match preview
After knocking out Monza away from home in the last round, Reggiana will hope to provide similar treatment to another Serie A side this midweek, but Genoa enter the game with confidence after a fine win over the weekend.
Nesta's 2006 World Cup winning teammate Alberto Gilardino saw his Genoa side beat Salernitana 1-0 on Friday night in the league's weekend opener, with Albert Gudmundsson netting the only goal.
That win took Genoa four points clear of the drop zone, and the Rossoblu faithful will have been glad to secure a stress-free three points after the amount of drama they have witnessed at Marassi this season.
They have already recorded 4-1 wins and defeats at home so far, as well as throwing away a 2-0 lead at home to champions Napoli.
The most dramatic fixture was when AC Milan left with all three points though, in a game which saw both goalkeepers sent off and Olivier Giroud finish the game in goal for the visitors.
Even Genoa's first round tie in this competition was a dramatic one, and it has been almost three months since they got the better of Modena, winning 4-3.
Il Grifone have often made light work of the early rounds in the Coppa Italia, not losing at this stage since 2007 when Ascoli knocked them out.
However, they do struggle to make it far, as seven of the last eight seasons have seen Genoa be eliminated at the last 16.
As an 87-year wait for a second Coppa Italia title goes on, the supporters would be delighted with just a deep run, as they have not even made a final since 1940.
Visitors Reggiana climbed back up to Serie B last season winning promotion after reforming in Serie D just five years ago following a second bankruptcy in 13 years.
Nesta was brought in as manager at the start of the campaign, and they showed very promising signs in his first two competitive games in charge which both came in this competition.
After hammering Pescara 6-2 in the qualifying round, Reggiana then stunned Monza 2-1 at the U-Power Stadium, setting themselves up with another trip to a Serie A outfit.
Early league form did not match the promise of those cup wins though, as it took Nesta six games to find his first league win.
However, Reggiana have improved greatly recently, only losing one of their last eight games and having won both of their previous two.
Thrashing bottom-of-the-table FeralpiSalo 3-0 at the weekend should give Nesta and his players plenty of confidence coming into this one in a game where they have very little to lose.
Genoa Coppa Italia form:
W
Genoa form (all competitions):
L
W
D
L
L
W
Reggiana Coppa Italia form:
W
W
Reggiana form (all competitions):
W
D
L
D
W
W
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Team News
Gilardino is likely to rotate given the quick turnaround they have before travelling to Sardinia to face Cagliari at the weekend.
Italy international Mateo Retegui went off at half-time in the win over Salernitana after picking up a knock, so he is likely to be rested with Caleb Ekuban and George Puscas the candidates to replace him.
Veteran midfielder Kevin Strootman made a cameo appearance in Friday's win, and in his return from injury could be given a start here.
Morten Thorsby and Berkan Kutlu could well join Strootman in midfield, while Ridgeciano Haps could also start at left wing-back after being an unused sub versus Salernitana.
Filip Jagiello and AC Milan loanee Junior Messias are Gilardino's only known injury concerns heading into this cup tie.
Nesta will have been delighted to see Janis Antiste net his first goal for the club at the weekend following his loan move from Sassuolo.
Manolo Portanova also played an important role in the weekend win, and he should feature against his parent club here.
There are plenty of other players with top-flight experience at Nesta's disposal too, including goalkeeper Francesco Bardi and wide man Domen Crnigoj.
Midfielder Luca Cigarini is set to start in midfield at the ground where he had a forgettable spell with Genoa's bitter rivals Sampdoria in 2016 - making just four appearances.
Genoa possible starting lineup:
Leali; Vasquez, Vogliacco, Dragusin; Sabelli, Thorsby, Strootman, Kutlu, Haps; Ekuban, Gudmundsson
Reggiana possible starting lineup:
Bardi; Szyminski, Rozzio, Marcandalli, Pieragnolo; Portanova, Cigarini, Bianco; Antiste, Gondo, Crnigoj
We say: Genoa 3-2 Reggiana
Genoa have witnessed many thrillers at home so far this season, including the 4-3 win over Modena in the last round, and even though rotation is likely, they should still progress here.