Rudi Garcia's men currently sit a point adrift of league leaders Juventus, having closed the gap with a 1-0 midweek victory at Udinese.
The Rome derby - one of the fiercest rivalries in European football - highlights this weekend's action and gives Roma a chance to climb above the defending champions - if only briefly ahead of Juve's meeting with Napoli later on Sunday.
Garcia's side will also revel in the chance to put real daylight between themselves and their neighbours and defender Davide Astori knows his side are entering a crucial period of the campaign.
"Now the fun begins, because we have closed the gap on the top of the table," he is quoted as telling Radio Roma.
"Every point now becomes important, not decisive, but really something to think about. On Sunday we have the first opportunity to go above Juventus.
"We have the ability to be a great team, we need results such as the ones which could occur on Sunday to boost our confidence."
Lazio are without are derby win in Serie A since November 2012, but did beat their arch-rivals in the 2013 Coppa Italia final.
Juve, meanwhile, will be eager to bounce back from their 1-1 home draw against Inter in midweek but face tricky opposition in fourth-placed Napoli.
Rafael Benitez's hosts come into the fixture fresh from back-to-back victories in the league, the latest a 4-1 thrashing of Cesena.
Sandwiched between those two Serie A triumphs was a Supercoppa victory over Juve on penalties in a game played in Qatar.
Genoa and Sampdoria currently sit three points adrift of the top four and face Inter and Empoli respectively this weekend.
Gianfranco Zola's start to life as Cagliari boss ended in an emphatic 5-0 defeat to Palermo on Tuesday, but the former Azzurri striker will have another chance to get off the mark in an important relegation clash with Cesena.
Basement club Cesena are currently three points adrift of Cagliari, but would pull level with a win at Stadio Sant'Elia.
Second-bottom Parma are at Verona, while struggling Atalanta and Chievo meet at Stadio Atleti Azzurri d'Italia.
Sassuolo will be looking to follow up a memorable scalp at Milan with victory at home to Udinese on Saturday, and Torino host Filippo Inzaghi's side on the same day.
In Sunday's remaining fixture, ninth faces eighth as Fiorentina play host to Palermo.
