For the first time, Iran is taking part in the discussions, where the future of Syrian president Bashar Al-Assad is high on the agenda.
The United States and Saudi Arabia want him out, but they face strong resistance from his key backers in Iran and Russia.
United States Secretary of State John Kerry has described the task ahead for the talks in Vienna on Syria's future as "charting a course out of hell."
He was not promising reporters any miracle solutions to the almost five-year-old crisis in Syria as he headed into another round of talks.
(Question:) "Mr Secretary, what do you expect to accomplish in Vienna?"
(Kerry:) "I'll tell you when we've accomplished it -- if ... if. We have a lot of very important meetings, we'll see what happens. Thank you. And we're very, very grateful to Austria for its incredible hospitality. Thank you."
A new key player at the Vienna meeting is Iran, which, like Russia, has been a staunch backer of the Assad government.
Foreign Minister Mohammad Javed Zarif says there were no preconditions on his participation in the talks.
He says, if there had been, Iran would not have accepted them.
"Any peace plan in Syria should have some phases, including a halt to the conflict, a collective battle against terrorism, a national-unity government and reaching a final solution through dialogue between the Syrian people and Syrian groups."
Saudi Arabian foreign minister Abdel Al-Jubeir says he is sceptical about Iran's motives in attending.
But he says the diplomacy is worth the effort, given what is at stake.
"The view of our partners in this was that we should test the intentions of the Iranians and the Russians about their seriousness in arriving at a political solution in Syria, which we all prefer because it will expedite the resolution of this human tragedy and this crisis."
With Germany and other European nations facing a record influx of refugees fleeing Syria, German chancellor Angela Merkel says ending the conflict is more important than ever.
"We need a diplomatic, political solution and, in view of the more than 300,000 dead and the millions of refugees in Syria, the time is urgent. And I am really happy there are at least signs of a format of talks that will bring the necessary participants together, and the faster the people in Syria can be helped, the better."
United Nations Secretary-General Ban Ki-Moon has called on the countries participating in the talks to put aside their own interests for the sake of Syria.
"I'm urging all these five countries to show their global leadership rather than their own national perspectives. The longer they take their own national perspectives, the much more people will suffer. And the whole world will suffer."
John Kerry, the US Secretary of State, says the talks represent the best chance of achieving a political transition in Syria.
"While finding a way forward on Syria will not be easy -- it's not going to be automatic -- it is the most promising opportunity for a political opening. We're recognising what is happening, that Syria's being destroyed."
Russia and Iran are fighting alongside the Syrian government forces against Saudi Arabian-backed and US-backed rebels, making any negotiations a particularly delicate balancing act.
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