Pep Guardiola's side needed a late goal to squeeze past Hoffenheim last time out in this competition and the men from Manchester will have to be at their best when they meet Paulo Fonseca's charges.
Shakhtar have an enviable home record in this competition, for they have lost just two of their last 12 matches on Ukrainian soil - against Real Madrid and Paris Saint-German respectively.
Nevertheless, Tuesday's hosts are chalked up as a chunky 11/2 (6.50) chance with William Hill to deal a significant blow to Manchester City's Champions League aspirations with a win in Kharkiv.
Guardiola's side cannot afford to falter after being beaten at home by Olympique Lyonnais in their opening group game and William Hill offer 2/5 (1.40) that the English champions claim a vital victory.
The same firm go 9/2 (5.50) that the match ends all square - both of Shakhtar's opening two group games have ended in a 2-2 draw.
Claudio Bravo, Danilo and Ilkay Gundogan are out for City, but Kevin De Bruyne is pushing for a starting spot after coming off the bench against Burnley at the weekend.
Brazilian winger Taison, is absent for the hosts after rupturing his knee ligaments earlier this month.
Shakhtar have scored 31 goals in 12 league matches so far this season - significantly more than any other side in the Ukrainian top tier.
Furthermore, Fonseca's men have scored two or more goals in 10 of their last 11 home matches in this competition.
City have scored in all but one of their last 17 Champions League matches - a sequence of results that includes a 2-1 defeat against Shakhtar in Kharkiv 10 months ago.
Both sides possess plenty of quality in attacking areas. What's more they are in need of a positive result to strengthen their prospects of reaching the knockout stage and as such there is plenty of potential for an explosive encounter.
William Hill's Even money (2.0) quote for four or more goals to be scored when these teams meet that could provide punters with a path to profit.