The UN-hosted negotiations, which began a day before the fifth anniversary of the outbreak of the conflict, are the latest effort to end violence that has killed more than 270,000 people and displaced millions.
As the delegations arrived in Geneva over the weekend, Damascus warned that any discussion about removing Assad would be a "red line".
Top Western diplomats immediately condemned the comment from Syrian Foreign Minister Walid Muallem as divisive and provocative.
Speaking earlier, he said the talks quickly needed to focus on "the real issues".
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"What is the real issue?" he asked. "The mother of all issues (is) political transition."
The UN envoy said the agenda for the negotiations will follow a Security Council resolution that calls for a transitional government to be formed in six months, and general elections within the following year.
A temporary ceasefire introduced on February 27 has largely held, despite accusations of violations from both sides, allowing aid to reach some 150,000 people living under siege.
The truce - the most significant since the conflict began - has sparked cautious encouragement. But experts warn that negotiations will still struggle to achieve a durable peace on the fractured battlefields where multiple groups are competing for dominance.
Representatives from Syrian Kurdish groups, which have played a key role in combatting jihadist fighters, have been excluded from the talks despite a push from Russia.
"Otherwise this cannot claim to be a representative forum," he was quoted as saying by the RIA Novosti state news agency.