Tottenham paid the price for a Dele Alli horror-tackle as Mauricio Pochettino's side drew 2-2 with Gent and crashed out of the Europa League last 32.
Trailing 1-0 from the first leg in Belgium, Spurs enjoyed the perfect start at Wembley when Christian Eriksen opened the scoring, only for a Harry Kane own-goal to pull the visitors level.
Then, in the 39th minute, came Alli's moment of madness as he lunged high into Gent's Brecht Dejaegere, leaving Spurs needing to score twice more with 10 men.
Victor Wanyama's superb second-half strike gave Tottenham temporary hope but it was all for nothing, as substitute Jeremy Perbet's late goal ensured Gent snatched a shock 3-2 aggregate victory.
It means Tottenham's Wembley woes continue - the attendance of 80,465 set a new Europa League record - but they have now won only once at the national stadium in their last eight matches. It does not bode well for next season, when they are due to play all their home games here.
More immediately, defeat also brings an end to an excellent chance of securing silverware this season and extends a disappointing showing more generally in this competition, where Spurs have now failed to go past the quarter-finals in any of nine attempts in the last 10 years.
Pochettino fielded his strongest available side, with only the injured Danny Rose and Erik Lamela absent, and the likes of Kane, Alli and Mousa Dembele all included.
The Argentinian said on Wednesday he knows within 50 seconds which Tottenham are going to turn up and he would have been buoyed by his side's start, typified by a thumping early challenge by Wanyama.
Ten minutes in, they were ahead, although not from any flowing move but rather a defensive mix-up from Gent, as three defenders failed to clear Kyle Walker's long ball over the top and Eriksen nipped in, before sliding past Lovre Kalinic at the near post.
Eriksen grabbed the ball out of the net, the job only half done, but when moments later Walker pulled back for Alli to finish wide, it seemed only a matter of time.
Set-pieces, however, have often been this team's undoing this season and so it proved again as Gent snatched an equaliser, Stefan Mitrovic heading the corner towards goal and a straining Kane inadvertently flicking it into his own net under pressure from Moses Simon.
Replays suggested Toby Alderweireld had been unfortunate to concede the corner but Tottenham, who now needed three, were the arbiters of their own misfortune soon after.
Alli had cut a frustrated figure throughout the first half and when he was denied another free-kick the red mist descended.
He sprung to his feet, miscontrolled the ball before spearing his right foot into the shin of Dejaegere. It was high and dangerous, and referee Manuel De Sousa had no option but to send the midfielder off.
Pochettino pushed Eriksen inside behind Kane, in a 3-4-1-1, and Spurs emerged with renewed vigour after half-time, the latter twice missing when he should have scored, first firing over when put through by Eriksen and then getting the ball stuck under his feet when five yards out.
It felt like Spurs needed to capitalise on their momentum and in the 61st minute they did, albeit from an unlikely source, as another sublime touch from Eriksen laid on Wanyama to bend a brilliant strike into the far corner.
Tottenham's tails were up, with substitute Son Heung-min particularly lively, although Gent could have put tie beyond doubt when Simon headed into the side-netting when free at the far post.
Pochettino was literally jumping on the touchline, spurring his side on, but with eight minutes left their hopes of a comeback were dashed.
Kalifa Coulibaly raced clear on the break and while Eric Dier stopped his cross, it fell perfectly for Perbet to prod home.
Vincent Janssen was thrown on in the dying minutes but the game was already up, as Tottenham's miserable European adventure drew to a close.