Ange Postecoglou suffered his first defeat as Tottenham boss as Fulham won 5-3 on penalties after a 1-1 draw in the League Cup second round on Tuesday.
Postecoglou had masterminded an encouraging start to his first season in charge of Tottenham, with successive Premier League wins against Manchester United and Bournemouth following a draw against Brentford.
But the former Celtic boss paid the price for making nine changes to his starting line-up at Craven Cottage.
Postecoglou handed a full debut to Manor Solomon, while Giovani Lo Celso and Pierre-Emile Hojbjerg started despite speculation over their futures.
Fulham boss Marco Silva, who served a touchline ban following his third yellow card of the season, made six changes himself, but it was Tottenham's understudies who struggled.
Micky van de Ven's 19th minute own goal gave Fulham the lead as the defender turned Tom Cairney's cross past keeper Fraser Forster.
Tottenham took advantage of a curious incident that left Fulham down to 10 men to equaliser in the 56th minute.
A problem with Kenny Tete's boot meant the Fulham defender had to sprint down the tunnel to find a replacement in the dressing room.
Moments later, Ivan Perisic whipped in a cross from the position Tete would have been defending and Richarlison headed home from an acute angle.
But Tottenham were unable to find a winner and in the shoot-out Davinson Sanchez's effort was saved by Marek Rodak before Tete, now with boots on both feet, fired the decisive kick.
Currently enduring a trophy drought that stretches back to 2008, Tottenham already have one less competition in which to end that barren run this term.
Luton beat fourth tier Gillingham 3-2 at Kenilworth Road to win for the first time this season.
After losing to Brighton and Chelsea in their first two Premier League games, Rob Edwards' side got off the mark in their first home game since winning last season's Championship play-off final.
Jacob Brown, Alfie Doughty and Cauley Woodrow scored for Luton, who are playing in the top-flight for the first time in 31 years.
- 'Absolutely incredible' -
Bournemouth boss Andoni Iraola earned his first win in English football as Ryan Christie's last-gasp goal clinched a 3-2 victory at second tier Swansea.
The Spaniard had overseen a draw with West Ham and defeats by Tottenham and Liverpool in his first three league games.
David Brooks and Hamed Traore netted for the Cherries before Ryan Christie's superb finish won it for Iraola in stoppage-time.
Brentford needed a 3-0 penalty shoot-out victory to advance after a 1-1 draw at fourth tier Newport.
Crystal Palace survived a scare against Plymouth as they fought back from two goals down to win 4-2 at second tier Plymouth thanks to Jean-Philippe Mateta's hat-trick.
Fourth tier Salford, co-owned by former Manchester United stars David Beckham, Gary Neville, Ryan Giggs and Paul Scholes, beat Leeds 9-8 on penalties after a 1-1 draw with the Championship club.
"Absolutely incredible. I would have never imagined this game to go so far, never mind to go to penalties and to win. Such a big night for all these Salford fans," Neville said.
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