Beaten in last season's final, the Serie A leaders are intent on going one step further this term, while their second-tier opponents aim to cause an almighty shock.
Match preview
Setting a new club record for successive Serie A wins, Atalanta took their winning streak into double figures on Saturday, as they edged out Cagliari thanks to Nicolo Zaniolo's goal and a series of Marco Carnesecchi saves.
Leading the Italian top flight by two points ahead of a large chasing pack, La Dea had suffered a rare setback a few days earlier - losing to Real Madrid in the Champions League - but normal service was resumed at the weekend.
Still vying for a top-eight finish in the league phase of Europe's top tournament, and leading the way in an enthralling title race, Atalanta can claim to be targeting four trophies this season, following last term's groundbreaking Europa League triumph.
Also set to take part in the Supercoppa Italiana next month, the Bergamo club will first start their latest cup campaign, returning to the Coppa Italia for the first time since losing 1-0 to Juventus in May's final.
Ever demanding, head coach Gian Piero Gasperini has tempered praise with words of caution as his team try to secure the club's first Scudetto, but Atalanta undoubtedly start favourites to reach the Coppa quarter-finals.
Having won four of the sides' last five league meetings since knocking Cesena out of the cup back in 2009, the Bergamaschi will expect to continue in that vein on Wednesday.
The winner of the clubs' first contest since 2015 will secure a home tie with Bologna in February's quarter-finals, but Cesena must cause a major upset in order to bring their Emilian rivals to Stadio Dino Manuzzi.
While Atalanta are just entering the competition due to their Champions League obligations, Michele Mignani's men have reached this stage of the Coppa by taking the scenic route.
After seeing off Padova in the preliminary round, they were handed a first-round tie away to top-flight opposition, and Cristian Shpendi scored the winner in a 2-1 victory over Hellas Verona at Stadio Bentegodi.
Then, Raffaele Celia's strike eliminated Cesena's fellow Serie B promotion contenders Pisa in September, since when they have returned to fighting for a top-eight finish in Italy's second tier.
After Saturday's 2-1 win over Cosenza, the Bianconeri sit fourth in the standings and are on course for a playoff spot, although 12 points separate them from the automatic promotion places as things stand.
Atalanta BC form (all competitions):
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Cesena Coppa Italia form:
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Cesena form (all competitions):
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Team News
Amid a packed schedule, Atalanta will surely take the chance to make multiple changes, with fringe players such as Nicolo Zaniolo and Lazar Samardzic being offered rare starts.
Serie A top scorer Mateo Retegui could be among those rested by Gian Piero Gasperini, though captain Marten de Roon may return after being benched at the weekend.
Giorgio Scalvini is struggling with a muscular problem and Gianluca Scamacca has yet to make his comeback from an ACL rupture, though fears about a serious chest injury to Isak Hien were quelled after returning from Cagliari; having sustained some bruising, the latter should also sit out Wednesday's game.
Meanwhile, Cesena have suffered a big setback before making the trip to Bergamo, as main marksman Cristian Shpendi left the pitch in tears during the win over Cosenza, and a sprained ankle could keep Serie B's leading scorer sidelined for several weeks.
Sydney van Hooijdonk is therefore be in line for promotion from the bench, potentially linking up with rising star Tommaso Berti, who scored the Bianconeri's crucial second goal on Saturday.
Sierra Leone striker Augustus Kargbo is another contender to deputise as the spearhead of a likely 3-4-2-1 formation.
Atalanta BC possible starting lineup:
Patricio; Djimsiti, Toloi, Godfrey; Palestra, De Roon, Pasalic, Zappacosta; Samardzic, Brescianini; Zaniolo
Cesena possible starting lineup:
Pisseri; Curto, Prestia, Mangraviti; Ceesay, Calo, Bastoni, Donnarumma; Berti, Antonucci; Van Hooijdonk
We say: Atalanta BC 3-0 Cesena
The most potent attack in Serie A will meet one of the least effective away sides in Serie B, so Atalanta can surely take care of business.
Written by
Jonathan O'Shea