Five years of this conflict have been too much. The horror is in front of everyone's eyes
But there are already signs of the hurdles ahead with the Syrian opposition insisting that they will not attend.
They say they have not received convincing answers to demands including an end to airstrikes and blockades.
“Five years of this conflict have been too much,” said De Mistura in an emotional plea to all sides. “The horror is in front of everyone’s eyes. You must know also that we count on you to raise your voice, to say ‘khalas’, it is enough.
You have seen enough conferences, two have already taken place. This one cannot fail.”
The Syrian government, who will send a delegation to the talks, is continuing to claw back territory from rebels with help from Iran and Russia.
As well as the estimated quarter of a million deaths around eleven million Syrians have been displaced.
Many have died in attempting to cross the sea to Europe, giving added impetus to the efforts to find a diplomatic solution to the conflict.