Victory for either would almost guarantee them fourth place in the Premier League and a lucrative spot in next season's Champions League.
Just one point separates current incumbents Spurs from City, so this is a must-win game for both clubs at a vital point in the season.
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City warmed up for this massive game with a 3-1 victory over Aston Villa on Saturday which ended the sixth-placed Midlands club's hopes of fourth spot.
Their attacking trio of Carlos Tevez, Emmanuel Adebayor and Craig Bellamy were all on the mark as City followed up a meek goalless draw with Arsenal and derby defeat to Manchester United in successive weekends with a performance to silence their doubters.
Immediately afterwards, manager Roberto Mancini set his sights on Spurs and it is no surprise with rumours continuing to circle that his stay at Eastlands will last just half a season should he fail to secure Champions League football for an ambitious board.
Veteran midfielder Patrick Vieira produced his best performance since joining in January and the former Arsenal skipper will be hoping to put one over Tottenham on Wednesday night.
However, Mancini is fighting the tide of a lengthy injury list with the likes of Shay Given (shoulder), Joleon Lescott (hamstring) and Martin Petrov (knee) all out and England midfielder Gareth Barry struggling to shake off a hamstring problem.
Tottenham also have a major injury concern of their own ahead of the trip to Manchester as number one goalkeeper Heurelho Gomes picked up a worrying groin knock in the closing stages of Saturday's 1-0 victory over Bolton Wanderers.
Youngster Ben Alnwick may have to be thrown into the fray of Spurs' biggest game in years should the Brazilian not recover in time.
Spurs though will certainly arrive in good form having defeated Arsenal and league leaders Chelsea before losing 3-1 at Manchester United ten days ago.
Most pundits had written off the chances of Harry Redknapp's side emerging from a horrendous run of fixtures still in the running for fourth place so confidence is certainly high at White Hart Lane.
Niko Kranjcar (ankle), Jonathan Woodgate (groin) and Carlo Cudicini (broken wrist) all definitely miss out with season-ending injuries while Vedran Corluka is a doubt with a sprained ankle.
Tottenham were comfortable 3-0 winners earlier in the season after two goals from Kranjcar and Jermain Defoe separated the sides in mid-December.
The defeat at White Hart Lane was also the final straw for the City board as they sacked Mark Hughes as manager just three days later - with rumours of impending firing coming during the following 4-3 home win over Sunderland.
Spurs won both encounters between these two clubs by 2-1 scorelines last season, while both won their home game by the same margin during the 2007-08 campaign.