Italian champion Nibali leads his main yellow jersey rivals by at least one minute 45 seconds as the race heads into its first mountain stint on Saturday and Team Sky will not be there to control the race as they did in the past two editions.
The Astana rider impressed with a brilliant display on the cobbles in Wednesday's fifth stage while most of the other top contenders struggled.
For those with designs on Nibali's place at the top of the general classification, a group that includes Alberto Contador, Jurgen van den Broeck, Andrew Talansky, Tejay van Garderen, Richie Porte and Alejandro Valverde, attack is the only option in the coming three stages.
"It's all for the taking, the Vosges are a fantastic place to attack, the stages have been well designed," Tinkoff-Saxo sports director Philippe Mauduit told Reuters.
His team leader, Contador, lies in 16th place overall, 2:37 off the pace.
Van Garderen's (18th at 3:14) BMC sports director Yvon Ledanois said: "The breaking point is here. There has been a lot of tension since the start of the Tour and there is a lot of fatigue already.
"That is why a lot of riders will crack in the Vosges."
Saturday's eighth stage takes the peloton to Gerardmer, with a short but steep climb leading to the finish line.
The biggest danger, however, could be the Col de la Grosse Pierre, a narrow climb with sections at a gradient of 16 per cent.
"The road is quite narrow and the gradient are sometimes impressive. It's a nice ascent, which will take some by surprise," said Mauduit.
Contador checked out the stage pre-race, but Nibali gave it a pass.
Sunday's trek from Gerardmer to Mulhouse features six categorized climbs but is probably not hard enough to motivate the top guns.
It should be a different story on Monday as the 10th stage ends at the top of La Planche des Belles Filles, a 5.9-km category-one ascent at an average gradient of 8.5 per cent that will be preceded by the brutal Col des Chevrieres (3.5-km at 9.5 per cent).
"Contador, Valverde and all will go on the offensive. It can start tomorrow," former pro Jean-Francois Bernard, who won eight grand Tour stages between 1986-90, told Reuters on Friday.
Bernard, who finished third overall in the 1987 Tour, believes Nibali will find it hard to defend his yellow jersey.
"I'm wondering how he is going to deal with the pressure, he does not have a very experienced team," the Frenchman said.
"Defending the jersey all the way to Paris? Well, good luck to them!"
Nibali is an aggressive rider by nature and he may well continue to push the pace.
"If there is an opportunity to attack, I will attack," he said on Thursday.
"The yellow jersey takes a lot of energy to defend but we will deal with it stage by stage."
In last month's Criterium du Dauphine, the top warm-up race for the Tour, Contador distanced Nibali in the climbs to finish almost two minutes ahead of the Italian in the general classification.
Nibali, however, looks much sharper than he was in June.
"It's not the same Nibali," warned Bernard.
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