"We need to deal with reality here... Mutual consent, which is what has brought us here, for a transitional government means that that government cannot be formed by someone that is objected to by one side or not," Kerry said in an opening statement.
"That means that Bashar al-Assad will not be part of that transitional government. There is no way, not possible in the imagination, that the man who has lead the brutal response to his own people could regain legitimacy to govern."
He was speaking as long-anticipated peace talks, bringing together the Syrian regime and the opposition for the first time, opened in the Swiss lakeside city of Montreux.
"One man and those who supported him can no longer hold an entire nation and the region hostage," said Kerry, who with his Russian counterpart Sergei Lavrov has led efforts to organise the peace conference since May.
"The right to lead the country does not come from torture, nor barrel bombs nor Scud missiles," the US top diplomat said.
"It comes from the consent of the people. And it's hard to imagine how that consent could be forthcoming at this important time."
But Kerry also stressed that in a new Syria there could be no place for the "thousands of violent extremists who spread their hateful ideology and worsen the suffering of the people".
He highlighted that there was a way forward already set out in the internationally agreed June 2012 Geneva communique which called for a transitional government in Syria agreed on by mutual consent.
The communique "is a peaceful roadmap for transition, and the only thing standing in its way is the stubborn clinging to power of one man, one family," Kerry said.
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