Speaking to reporters in Geneva, Staffan de Mistura stressed the importance of getting the talks quickly focused on "the real issues," adding: "What is the real issue? The mother of all issues (is) political transition."
"This is the moment of truth," he said before his first official meeting with the Syrian government delegation.
The long-awaited talks, which open on the eve of the fifth anniversary of the outbreak of the conflict, mark the latest bid to end the bloodshed that has killed more than 270,000 people and displaced millions.
Analysts say much has changed since the last round collapsed in February, but that the huge government-opposition divide will complicate a settlement.
Signup to our newsletter and follow us on Facebook and Twitter!
The central obstacles are the fate of President Bashar al-Assad, presidential elections and the type of new government.
A temporary ceasefire introduced on February 27 has largely held, despite accusations of violations from both sides, offering some reprieve for Syria's people and allowing aid to reach some 150,000 living under siege.
But experts have cast doubt on whether the talks will make progress and, if they do, whether any agreement will be able to take hold on the fractured battlefields where multiple groups are competing for dominance.
De Mistura said that he expected the talks set to begin Monday would be the first of three rounds.
The current one is expected to last until March 24, with a second round beginning after a recess of a week or 10 days, with that round lasting "at least two weeks."
A third round would be held after another recess, he said.
"By then, we believe that we should have at least a clear roadmap. I'm not saying an agreement, but a clear roadmap, because that is what Syria is expecting from all of us."