Facing a two-goal deficit, the Giallorossi have it all to do as they host Lyon in the second leg of their Europa League clash on Thursday.
Can the Giallorossi continue a string of impressive comebacks in European competition in recent weeks, and send their adventure onwards to the quarter-finals?
The Giallorossi got back to winning ways at the weekend, beating struggling Palermo 3-0 to pick up a valuable three points.
Stephan El Shaarawy, Edin Dzeko and Bruno Peres grabbed the goals, as Luciano Spalletti rotated his side somewhat. The result means Roma remain second in the Serie A standings, eight points behind leaders Juventus.
Meanwhile, on the same day Lyon were beating Toulouse at Parc OL, delivering a 4-0 victory that was highlighted by Memphis Depay's 50-yard goal.
The Dutchman got on the scoresheet twice in the game, as Maxwel Cornet and Christophe Jallet also found the back of the net.
Les Gones remain fourth in Ligue 1, 18 points behind leaders Monaco with a game in hand.
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Roma have almost a full squad to choose from, with Antonio Rudiger back after suspension and Emerson Palmieri, Bruno Peres and Diego Perotti all considered fit enough to be included in the squad despite slight injury concerns this week.
Alessandro Florenzi (injury) and Clement Grenier (ineligible) are the two senior absentees.
Lyon are also without any major injury doubts - the ineligible Memphis Depay (fresh off his goal from the halfway line at the weekend) the one obvious absentee.
Luciano Spalletti: “You have to closely analyse what happened in the first leg and weigh that up against what we need in terms of a result. Another thing that comes into it is the decisions we got wrong in the away match. I saw lots of things that we did well but we need to look at what didn’t go right because we can change that and work on it.
"Our desire will be sky high tomorrow night – we certainly won’t be wandering around the pitch.”
Bruno Genesio: “"I read in the paper that we've got a 67% possibility of getting through the round, but statistics count for nothing in football; you need to play the game on the pitch.
"We've got a lead and tomorrow will be a different game. We want to give it our best shot."
A goalscorer in the first leg at Parc OL, Tolisso was also one of the key performers on the pitch - impressing in midfield as Les Gones finished so strongly in the second half.
Called up to the France squad for the first time on the eve of the game, the youngster will be particularly keen to show that he deserves such recognition - and will be eager to show that his relative lack of experience is no issue as he comes up against the likes of Kevin Strootman and Daniele De Rossi on a highly-charged European night.
Lyon's attacking quality is well-known, but it is defensively that they will have to retain their structure and solidity if they are to progress from this second leg. Tolisso, as one of the primary enforcers in midfield, will have a huge role to play in that regard.
Read more about the head-to-head battle between Tolisso and Nainggolan.
The terms of this game are clear to all: Roma need to score at least twice if they are to progress. Edin Dzeko is the club's top goalscorer this season, having reached 30 goals already - so it stands to reason that he will likely need to have a big game if the Giallorossi are to be in Friday's quarter-final draw.
The striker will acknowledge himself that he did not make the biggest impact in the first leg, so he will be particularly keen to make amends and help his side turn the tie around. While his hold-up play will be crucial in releasing his attacking teammates and opening up the Lyon defence, it is inside the box where he will have to take his chances.
The 30-year-old knows from experience that nothing is certain in football - and will be hoping to help his side emulate Barcelona's historic comeback against Paris Saint-Germain and shock another French side.
“Of course. Anything’s possible in football and I haven’t changed my mind on account of [the Barcelona game]," Dzeko said. "When I was at [Manchester] City, we won the club’s first league title in 40 years in the last four minutes of the last game. We were 2-1 down in the first minute of added time against QPR, but we pulled it back to 2-2 and then [Sergio] Aguero scored to make it 3-2 and win the title.
"That’s football – everything is possible. I’ve always believed that.”
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Spalletti faces a selection decision over both shape and personnel, given his statement at his pre-match press conference that left-back Emerson Palmieri would likely not be fit to start the game.
Does he instead go with Mario Rui, who played his first 90 minutes for the Giallorossi on Sunday at Palermo, or - given Bruno Peres' slight injury concern this week - does he shift to a four-man defence for this one?
Elsewhere Alisson is likely to continue in goal, while Daniele De Rossi and Kevin Strootman will presumably occupy the key midfield berths. Kostas Manolas would also seem almost certain to return after being suspended at the weekend.
The temptation for Genesio will surely be to stick with the same line-up that secured the first leg advantage, reasoning perhaps that there is little point in tinkering with a successful formula.
However, given the dynamic of the clash, he may be tempted to put his side out in a more counter-attacking shape - with perhaps Maxwel Cornet and Nabil Fekir playing from the start this time to give the visitors more pace and incision on the counter.
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