Astana's Vincenzo Nibali took back the yellow jersey just one day after losing it to Tony Gallopin (Lotto-Belisol).
Nibali attacked on the final climb of La Planche des Belles Filles to win the stage, but the main story of the day centred around Alberto Contador (Tinkoff-Saxo).
The two-time Tour winner suffered a crash during the stage, and despite a valiant attempt to ride on was forced to abandon the race.
His team manager Bjarne Riis said after the stage that his leader had suffered a fractured tibia in the fall.
Contador followed defending champion and pre-race favourite Chris Froome (Sky), who withdrew on Wednesday, out of the race, leaving Nibali as the only one of the so-called 'serious contenders' left on the road.
And the Italian national champion did his credentials no harm at all with a fine victory.
Inside the final five kilometres, he first chased down lone leader Joaquim Rodriguez (Katusha) before going on the attack himself. Rodriguez, in his comeback race following a nasty crash in the Giro d'Italia, tried to stay on Nibali's wheel but the Astana man was too strong for the man who finished third last year.
The result means Nibali now has an advantage of 2'23" over Richie Porte (Sky), who lies in second place. Movistar's Alejandro Valverde is a further 23 seconds back in third.
Tuesday sees the first rest day of the 2014 Tour. The race continues on Wednesday with the peloton tackling a 187.5 kilometre route from Besançon to Oyonnax.