For the second time in three Group B outings, Tottenham were undone by a late goal in Eindhoven as Luuk de Jong found a way through in the 87th minute to rescue PSV a point in that reverse fixture a fortnight ago.
Spurs were also minutes away from beating Inter Milan in their opener, only for a couple of late goals to deny them a valuable victory on their travels. Those disappointing results sandwiched a 4-2 loss to Barcelona on home soil, leaving Mauricio Pochettino's men with it all to do.
With just a point to their name from three matches, Tottenham - and indeed opponents PSV - face the prospect of being dumped out of UEFA's elite club competition this week should they fail to win and Inter pick up victory at home to Barcelona.
Pochettino will not give up hope just yet, though the Argentine knows that his side will need to beat PSV, Inter and possibly Barcelona if they are to claim a top-two spot and progress through to the last 16 for the second year running.
Spurs, competing in the Champions League for a fourth time, are winless in five European matches and have lost three of those, including their last two at Wembley to Barcelona and Juventus.
The Lilywhites' struggles on the continent have put a blemish on what has been a strange campaign, as Pochettino's men have made their best start to a Premier League season, sitting fourth in the division on 24 points from 11 matches, yet even the manager admits that the mood has been low.
A failure to bring in any new players in the summer, combined with off-the-field issues regarding their new stadium, is to blame for the ongoing negativity. To the players' credit, though, they continue to power on, as witnessed in Saturday's 3-2 win at Wolverhampton Wanderers.
That triumph made it back-to-back wins for Tottenham, having also defeated West Ham United in the EFL Cup last 16, and they have now picked up victory in seven of their 10 away matches in 2018-19.
Winning at Wembley has not been so easy, however, failing to win successive matches there since August, and anything less than three points on Tuesday will signal the end of their latest European adventure.
Recent form in Champions League: LLD
Recent form (all competitions): WWDLWW
The 2-2 draw with Tottenham may have felt like a point gained in the grand scheme of things for PSV, but that was ultimately a match that they needed to win to keep alive their hopes of progressing into the last 16 for just a fourth time.
European champions in 1988, the Red and Whites have struggled when reaching the Champions League proper in recent times, going 11 matches without picking up a victory in this competition.
Away from home, meanwhile, the Dutch giants - winners of their domestic league for a 24th time last season - have failed to win since a 1-0 success at CSKA Moscow in November 2007. That is a run spanning 11 matches, losing eight of those.
PSV's record away to Premier League clubs does not make for good reading, either, as they have won just once on their last nine visits to England, although they did record a goalless draw at Old Trafford in 2015-16.
However, a rare away success on Tuesday, combined with a Barcelona victory at San Siro, will massively boost the Red and Whites' chances of finishing in second place. Should those results happen, PSV will trail Inter by just two points, with the two sides scheduled to face off on December 11 in the final round of matches.
Mark van Bommel has already seen his side thrashed 4-0 by Barcelona in their Group B opener, although that scoreline does not tell the whole story as Barca were not exactly dominant, before losing 2-1 at home to Inter through goals from Radja Nainggolan and Mauro Icardi.
PSV's domestic prospects look a lot more positive, however, as they are one of only two European sides - the other being Paris Saint-Germain - to boast a perfect record in their respective league.
A fourth Eredivisie title in five years would be nice; overturning massive odds to progress through to the last 16 of the Champions League would be equally sweet. For that to happen, PSV quite simply need to leave Wembley with all three points.
Recent form in Champions League: LLD
Recent form (all competitions): WWDWLW
Pochettino may therefore be forced to shuffle his pack in central midfield, possibly meaning a partnership of Harry Winks and Moussa Sissoko, but he does at least have a full complement of options in attack following Dele Alli's recent return to action.
In terms of the visitors, Van Bommel can call upon Steven Bergwijn for this tie as the Premier League-linked winger is back involved after sitting out the 2-2 draw two weeks ago.
De Jong's goal against Vitesse at the weekend made it four in four for him, and Van Bommel will see no reason to change things in that department.
The Dutch side have picked a settled starting lineup for their past few matches, so Bergwijn's return for Donyell Malen may be the only change made from their most recent European outing.
Tottenham Hotspur possible starting lineup:
Gazzaniga; Trippier, Sanchez, Alderweireld, Davies; Sissoko, Winks; Son, Eriksen, Lucas; Kane
PSV Eindhoven possible starting lineup:
Zoet; Dumfries, Schwaab, Viergever, Angelino; Rosario, Hendrix; Lozano, Pereiro, Bergwijn; De Jong
Head To Head
Prior to last month's four-goal draw in Eindhoven, these two sides had met on just two previous occasions.
That double-header came in the 2007-08 campaign when Spurs and PSV claimed 1-0 away wins in their UEFA Cup last-16 tie, with the latter going through 6-5 on penalties.
Tottenham's last home game against visitors from the Netherlands ended in a 4-1 defeat of FC Twente in the 2010-11 group stage. In fact, their only loss to Dutch opposition on home soil was the 1-0 reverse to PSV a decade ago.
We say: Tottenham Hotspur 2-1 PSV Eindhoven
Victory will be the target for both sides, knowing that anything less could officially bring an end to their Champions League campaigns. Both teams have impressed domestically, losing three games between them, but Tottenham will be confident of maintaining their positive record against Dutch sides on home soil.