Benedict left from Rome's Leonardo da Vinci airport at around 9:40 a.m. (0740 GMT, 3:40 a.m. EDT).
His meeting with church officials from across the region could, however, be overshadowed by the death of Bishop Luigi Padovese, the church apostolic vicar in Anatolia, who was killed Thursday. Officials have identified the killer as the bishop's driver and say it was not politically motivated. On Friday, a Turkish court said the driver was charged with murder and jailed pending trial.
The Vatican spokesman, the Rev. Federico Lombardi, said Padovese's killing shows the "difficult conditions" the Catholic community faces in the Middle East.
The pope is meeting in Cyprus with prelates from the region to set an agenda for an October meeting in Rome to build a strategy to stem an exodus of Catholics from the Holy Land, Iraq and elsewhere because of violence and economic hardship. The Middle East includes ancient Christian communities.
The October meeting shows "how the universal church is in solidarity with this community," Lombardi said.
Benedict also faces issues on the division in Cyprus, splits in the Orthodox Christian community and concerns over damaged Christian and Muslim houses of worship. Cyprus was ethnically split in 1974 when Turkey invaded after a coup by supporters of union with Greece. Turkish Cypriots declared an independent republic in the north in 1983, but only Turkey recognizes it and maintains 35,000 troops there.
The trip also comes days after the island's leaders -- Greek Cypriot President Dimitris Christofias and the newly elected president of the breakaway Turkish Cypriots, Dervis Eroglu -- resumed peace talks after a two-month pause.
Police say hundreds of police will be on duty to provide security, including riot police in the event of any trouble -- which authorities consider "remote."
There are no plans for Benedict or any other Vatican officials to visit northern Cyprus, Lombardi said. But he did not rule out a meeting with Muslim representatives.
The Cypriot ambassador to the Holy See, George F. Poulides, said Benedict will be staying at the Vatican Nunciature, located right on the so-called Green Line in Nicosia -- the U.N.-patrolled buffer zone between bullet-pocked buildings and army sentry posts separating the ethnically divided communities.
A government official in Ankara said Turkey would be watching the visit closely and may comment if there is indication of political support for the Greek Cypriots or any allusion to the alleged destruction of churches in the north.
During a 2006 Vatican audience, the late Cypriot President Tassos Papadopoulos gave the pope an album of photographs of destroyed churches in the north and of others converted to restaurants, shops or other secular uses.
The Turkish north has published a book showing the destruction of mosques, cemeteries and other signs of Turkish culture in the south.
There are also problems between Cypriot Catholics and Orthodox Christians, who are dominant in the south. Some hardline Orthodox clerics, who view the pope as a heretic, say Benedict should stay in Rome to avoid provoking the island's 800,000 Orthodox.
Benedict on Sunday said he was "making an apostolic journey to Cyprus, to meet and pray with the Catholic and Orthodox faithful there."
Doctrinal, theological and political differences caused the Orthodox and Catholic churches to formally split in the 11th century. Officials from both churches have been engaged in talks in recent years to heal "The Great Schism," but opposition to reconciliation still lingers.
Archbishop Chrysostomos II said such critics "can stay at home" if they don't like the papal visit, which most church leaders have welcomed.
Early on Friday's schedule was an ecumenical prayer service. He will also meet with the president and diplomatic corps as well as the island's small Maronite and Roman Catholic communities.