The teams have shared fourth place in the Premier League since the end of December, and Liverpool's season-long slump has left them with the opportunity to reach the Champions League for the first time.
With just one point separating City from Spurs above, success in finally making it into club football's most lucrative competition could simply be down to which team deals best with the pressure of what is, financially at least, more important than a cup final.
“We didn't go into the season expecting; we were hoping,” Tottenham manager Harry Redknapp said. “We all felt that if one team would break into the top four this year, realistically it would be Manchester City. With the resources and money they spent.
“So there's no real pressure on us.” Even so, Tottenham playmaker Luka Modric won three league titles in Croatia with Dinamo Zagreb but says the game may be the biggest he has ever played in club football “This is probably the game of the season,” Modric said.
“In fact, not 'probably.' It's definitely the game of the season for both us and them.” Most of Tottenham's players have experience of big occasions, having reached the League Cup final in 2008 and 2009, while City's costly squad stumbled at its first major hurdle - losing a two-legged semifinal in the same competition to Manchester United in January.
City's 200 million-pound ($304 million) expenditure on players over the past two years is far in excess of Tottenham's outlay over the same period, but a poor run of form at the end of 2009 and a change of coach stymied progress.
That loss to United denied City a long-awaited appearance in a major final but City manager Roberto Mancini is unconcerned.
“It's going to be a final,” Mancini said. “We wanted one final this year and we have it. Now we must win against Tottenham.
“It's maybe the most important game in the last year and we must win.” Both teams have showed flashes of devastating attacking verve this season - Tottenham mauled Wigan 9-1 before beating Arsenal and Chelsea two weeks ago, while City has beaten Chelsea and Arsenal on its way to racking up 72 goals from 36 Premier League games - but the crucial position on the field on Wednesday could be in goal.
Tottenham goalkeeper Heurelho Gomes injured his groin in Saturday's 1-0 win over Bolton and, with backup Carlo Cudicini still out following a motorcycle accident, third-choice Ben Alnwick may start his first Premier League match.
And a season-ending elbow injury to Shay Given led to Manchester City drafting in former Spurs 'keeper Marton Fulop on loan from Sunderland.
Alnwick looked shaky in the League Cup last season and Fulop equally so in his City debut against Aston Villa on Saturday.
Tottenham has already made it to its best ever Premier League tally of 65 points, just a season after opening a campaign by flirting with relegation.
“The disappointment we shall all feel if we do not make the fourth qualifying spot for Champions League, will be a measure of exactly how far we have come,” Tottenham chairman Daniel Levy said.
That turnaround has mostly come from Redknapp's ability to coax improved showings from players who were lacking confidence and under performing under his predecessor, Juande Ramos.
In Wednesday's other match, Fulham continues its warm up for next week's Europa League final with a home match against Stoke.
Neither team is in danger of relegation or in contention for European competition, so the match mainly represents a chance for Fulham players to impress manager Roy Hodgson ahead of the May 12 match in Hamburg.