It is a case of now or never for Lyon's 2015-16 Champions League hopes as they host a Gent side desperate for three points to keep their own chances of reaching the knockout stages intact.
Lyon have endured a miserable European campaign thus far with their only point coming against the Belgian champions in the reverse fixture on matchday one.
Despite their poor form, Lyon can still qualify and victory over Gent - coupled with Valencia failing to beat Zenit - would leave a winner-takes-all contest on matchday six against the Liga side.
However, a Valencia win in Russia would eliminate Lyon regardless of their result at the Stade de Gerland, which will host European football for the final time ahead of Lyon's move to the Stade des Lumieres next year.
Hubert Fournier's side - who have lost both of their home matches without scoring a goal - head into the contest on the back of a disappointing 3-0 Ligue 1 defeat at Nice.
The loss followed an excellent 3-0 win over Saint-Etienne in the Rhone derby before the international break, and left goalkeeper Anthony Lopes fuming ahead of the crucial Gent clash.
"We lacked aggression. It is infuriating," he told Lyon's official website. "We have to rectify this on Tuesday. There is hope that this is just an accident."
Gent will travel to Lyon without the backing of their away supporters, who have been banned from attending the match by local police as a precaution following the terror attacks in Paris earlier this month.
A total of 130 people are confirmed to have died as a result of a series of attacks across the French capital, with Belgium becoming a focus of the subsequent investigation.
Belgian champions Gent, who are playing their first Champions League campaign, are still well in contention to make the round of 16 and are just two points off second-placed Valencia.
Defeat to Lyon coupled with a Valencia win at Zenit would extinguish their hopes, but victory would leave it all to play for in the final group matches.
A 5-0 battering of Westerlo on Friday will give Gent plenty of confidence ahead of their trip, but head coach Hein Vanhaezebrouck warned that Lyon pose an entirely different threat.
"The team was good, if you [win] 5-0 it has to be the case," he said. "The start was perfect. [But] you cannot compare competitions."
Maxime Gonalons' sending off against Zenit last time out means his is suspended for Lyon, while Thomas Matton (foot), Hannes Van Der Bruggen (stomach muscle) and Nicklas Pedersen (ankle) are absent for Gent.
