The in-form pair will be on opposing sides on Sunday (1930 GMT) in the hotly-contested Genoa derby, a rare occasion for the two famous Italian clubs to snatch back some of the limelight from the dominant trio of Inter Milan, AC Milan and Juventus.
Genoa are the oldest surviving Italian soccer club having been founded in 1897 while Samp shook up the Serie A order by winning the 1991 title and reaching the 1992 European Cup final.
Sampdoria finished sixth last term and reached this season's UEFA Cup, where they still have a chance of going through to the knockout phase despite Wednesday's 3-0 defeat at Standard Liege.
Their success last term was largely down to playmaker Cassano, who joined from Real Madrid and was so influential that he bagged a late spot in Italy's Euro 2008 squad.
Many wondered if the colourful 26-year-old could continue his fine form this season, but he has again wowed fans with his close control, beautiful goals and creative spark.
"He is the one who can break the deadlock, by creating and finishing," Genoa midfielder Thiago Motta, who will have to mark Cassano, told reporters.
Despite Cassano's contribution, Samp are languishing in the bottom half with 16 points from 13 games and look up at seventh-placed Genoa with envy.
Genoa have won six and drawn one of their seven home league games thanks to the goals of Argentine Milito, who joined from Real Zaragoza despite interest from a host of bigger clubs.
He is Serie A's top scorer with 11 goals but Brazilian Motta, another surprise close-season signing having played for Barcelona and Atletico Madrid, thinks teamwork is the key.
"Diego is showing that he is an extraordinary player, born to score goals. But to arrive at that level, believe me, even he needs the help of his team mates," he said.
Genoa have not won away this term and on Sunday they are the visitors at the Marassi, which they share with Samp.
Juventus fans will argue that Alessandro Del Piero, who scored his 250th club goal in last weekend's 4-0 win over lowly Reggina, is the real revelation of the season at 34-years-old.
Juve, joint-second with Milan and six points behind leaders Inter, visit struggling Lecce on Sunday (1400).
Milan, beaten by Lazio in Wednesday's Italian Cup last 16 having lost 3-1 at Palermo in the league on Sunday, host Catania while Inter have a tricky trip to Lazio on Saturday (1930).
