Cypriot President Nicos Anastasiades and Turkish Cypriot leader Mustafa Akinci, who have negotiated for more than 18 months in the run-up to the talks, arrived separately at UN headquarters in Geneva before sitting down for talks.
The two leaders, who have been among the most outspoken proponents of a deal, smiled at the cameras before settling around a large table with their extensive delegations and delving into the thorny talks.
If that goes to plan, they will be joined from Thursday by the leaders of the island's three guarantor powers -- former colonial ruler Britain, Greece and Turkey.
But both sides acknowledge key issues still need to be thrashed out, with the prospects of solving one of the world's longest-running geopolitical disputes remaining murky.
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The United Nations has pulled out all the stops in its bid for a deal, eyeing the best chance of a settlement in more than a decade.
But some experts believe the Geneva talks are a disaster waiting to happen because of deep divisions on core issues such as property, territorial adjustments and security.
Leaving for Geneva on Sunday, Akinci described the talks as a "crossroads".
"We are not at a point where Geneva will mark the final conclusion. We need to be cautious," he said.
Anastasiades tweeted that he was heading to Geneva "with hope, confidence and unity" after earlier striking a note of caution, warning of "significant differences on substantive issues fundamental to a Cyprus solution".
Cyprus, home to around one million people, has been divided since 1974, when Turkish troops invaded the island in response to an Athens-inspired coup seeking union with Greece.