A point would be enough to see Leipzig advance to the last-16, although they need to win to stand any chance of overtaking Real Madrid at the top of Group F.
Match preview
Successive 1-1 draws against Real Madrid and Celtic for Shakhtar have seen Leipzig take control of the driving seat in Group F in terms of advancing alongside the holders, but the Ukrainians' destiny still remains in their own hands ahead of Wednesday's clash in Warsaw.
Having stunned Leipzig 4-1 away from home on matchday one, head coach Igor Jovicevic will have plenty of confidence that his side can overcome the Germans once again and claim a place in the knockout rounds for the first time in five seasons.
After dropping two points at home against FC Oleksandriya on Friday to allow Dnipro-1 to open up a five-point lead at the top of the Ukrainian Premier League, Jovicevic's players will be determined to bounce back and make their war-torn country proud to have a representative competing in the last-16 of Europe's elite competition.
Without true home advantage on their side, doing so may be more difficult for them than any other team in the tournament, but that particular element of adversity is something that Shakhtar are used to by now having been forced to play away from their home in Donetsk since Russia invaded Crimea in 2014. Indeed, their last league match was even interrupted due to an air raid siren, with both sets of players returning to their dressing rooms until it was safe to return to the pitch.
The odds are clearly even further against them given Leipzig's recent form as well as superior individual quality and collective resources, but emotion and spirit can make strange things happen in sport and Wednesday may end up being one of those nights.
However, Leipzig will be fighting tooth and nail for a place in the last-16, too, especially given that they head to Poland on a nine-match unbeaten run in all competitions since returning from the international break.
Marco Rose - who was appointed as the club's manager in early September - has more effectively instilled his methods in recent weeks after an understandably inconsistent opening few weeks of his tenure, with their 2-0 win against Bayer Leverkusen on Saturday moving them up to sixth in the Bundesliga table and within three points of the top four.
Ensuring that they qualify for next season's Champions League will be Rose's primary aim this season, but returning to the knockout stages will also be high on the list - alongside retaining the DFB-Pokal - after the club missed out last season before losing to Rangers in the Europa League semi-finals.
After their heavy defeat to Shakhtar at the Red Bull Arena, which led to Rose's predecessor Domenico Tedesco's sacking, Leipzig would almost certainly have taken needing a point against the Ukrainians on the final matchday in order to advance. Their mission on Wednesday is clear: avoid defeat at all costs.
Shakhtar Donetsk Champions League form:
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Shakhtar Donetsk form (all competitions):
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RB Leipzig Champions League form:
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RB Leipzig form (all competitions):
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Team News
Shakhtar will remain without Marian Shved and Viktor Kornienko due to injury in midweek, but otherwise Jovicevic appears to have a full squad to select from.
Lassina Traore, Mykola Matviyenko and Heorhiy Sudakov all came off the bench during Saturday's disappointing draw in Lviv, with the trio likely to return to the starting XI on Wednesday.
Leipzig, meanwhile, will travel without Mohamed Simakan, Yussuf Poulsen, Peter Gulasci, Konrad Laimer and Lukas Klostermann due to injuries.
With his side only requiring a point to reach the next stage, Rose could adopt a more cautious approach than his usual attacking line-up, meaning Andre Silva and Dani Olmo may have to settle for a spot on the substitutes' bench.
Shakhtar Donetsk possible starting lineup:
Trubin; Konoplya, Bondar, Matviyenko, Mykhaylichenko; Bondarenko, Stepanenko, Sudakov; Zubkov, Traore, Mudryk
RB Leipzig possible starting lineup:
Nyland; Henrichs, Orban, Gvardiol, Raum; Schlager, Kampl, Haidara; Szoboszlai, Nkunku, Werner
We say: Shakhtar Donetsk 1-3 RB Leipzig
We expect Shakhtar to push their opponents all of the way in Warsaw on Wednesday, but game state could play a large part in terms of dictating which direction the result heads in.
Providing that Leipzig can avoid falling behind early on, gaps should open up as the Ukrainian Premier League runners-up push for a winner, with the likes of Timo Werner and Christopher Nkunku perfectly placed to punish them in transition should that be the case.