Milan takes centre stage on Sunday night as the city's two football giants face off at the San Siro with top spot in Serie A up for grabs, while troubled Napoli try to reset after the international break.
Inter Milan lead the pack, on goal difference from Roma, as Italy's top flight returns to the iconic arena after it hosted the national team's bracing defeat to Norway last weekend.
Cristian Chivu's team are two points ahead of AC Milan, who sit behind Roma in third place and ahead of the weekend's headline clash.
Inter have won 11 of their last 12 matches in all competitions, their one defeat in that run coming at Napoli last month, and have established themselves as favourites for the Scudetto.
After the derby Inter travel to Atletico Madrid where they can put one foot in the last 16 after winning all four of their previous European matches.
Marcus Thuram could make his first start for Inter since September after fully recovering from a hamstring injury which caused him to miss out on France's World Cup qualifiers last week and in October.
But Denzel Dumfries is likely to miss the derby with an ankle injury, meaning Carlos Augusto will switch from the left flank to provide width.
Milan meanwhile have Adrien Rabiot back from his calf injury picked up on international duty with France last month, with coach Massimiliano Allegri hoping both he and midfield partner Luka Modric will play their first Milan derby.
Champions Napoli are level on 22 points with Milan, but even though they are firmly in the title battle all is not well in Naples, with Antonio Conte being given a few days away to cool off during the international break.
Conte exploded with anger after Napoli's 2-0 defeat at fifth-placed Bologna, who are only three points from the summit ahead of their trip to Udinese on Saturday.
The 56-year-old said that he wasn't prepared to "accompany the dead", a reference to a team he said lacked heart and one that sparked rumours of him resigning before Saturday night's visit of Atalanta.
Conte will be without key midfielder Andre-Frank Anguissa who suffered a hamstring injury with Cameroon, a knock which will keep him out until next year and infuriated Napoli owner Aurelio De Laurentiis, who demanded compensation to clubs who lose players to injury while they are away with their countries.
Also on Saturday, Luciano Spalletti recommences his bid to revive Juventus at rock-bottom Fiorentina, where the 66-year-old played at youth level in the 1970s.
Spalletti was born near Florence and Began his long managerial career up the road at Empoli over 30 years ago, and he returns to Tuscany with Fiorentina bottom of the division and desperate to turn their season around under new coach Paolo Vanoli.
PLAYER TO WATCH: Ademola Lookman
It has been a troubled season for Lookman, caused in part by his pushing for a summer move to Inter which led to him being frozen out by Atalanta's former coach Ivan Juric.
But with Juric sacked and Raffaelle Palladino now in place it could be a new start for the Nigeria forward against Napoli in Naples.
Lookman, who has only scored once since being brought back into the fold in September, was the star of Gian Piero Gasperini's final Atalanta team, and he will be key if Palladino is to pull the Bergamo club out of their current funk.
The 28-year-old showed clear unhappiness with Juric after being substituted during Atalanta's Champions League win at Marseille but under Palladino has a chance to turn over a new leaf.
KEY STATS
6 - The number of points which separate league leaders Inter from Juventus in sixth.
5 - Hakan Calhanoglu and Riccardo Orsolini lead the scoring charts with five goals, with 12 players below them on four.
Fixtures
Saturday
Cagliari v Genoa, Udinese v Bologna (4pm), Fiorentina v Juventus (7pm), Napoli v Atalanta (9:45pm)
Sunday
Verona v Parma (1:30pm), Cremonese v Roma (4pm), Lazio v Lecce (7pm), Inter Milan v AC Milan (9:45pm)
Monday
Torino v Como (7:30pm), Sassuolo v Pisa (9:45pm)