Pope Francis headed to Cuba on Friday looking to heal a 1,000-year-old rift in Christianity before embarking on a tour of Mexico dominated by modern day problems of drug-related violence and migration.
The Argentinian pontiff took off from Rome's Fiumicino airport shortly before 8:00am (0700 GMT) en route to Havana, where he is to spend around two hours in private conversation with Russian Orthodox Patriarch Kirill at Havana's Jose Marti airport.
It will be the first meeting between the leaders of Christianity's two biggest churches since a 1054 schism that helped to shape modern Europe and the Middle East.
Francis and Kirill are due to sign a joint declaration on the contemporary persecution of Christians in places such as Iraq and Syria.
The meeting on neutral ground has been decades in the planning, with the final obstacles finally swept away by a combination of the pope's determination that it should happen and the Russian church's feeling that events in the Middle East have made Christian unity much more urgent.
The rapprochement with the Orthodox wing of Christianity is in line with Francis's drive to make the Vatican a more active player in international diplomacy.
"I just wanted to embrace my Orthodox brothers," he said in an interview this week. But he also framed the encounter in a broader context of engaging Russia, saying Moscow could be an important partner for peace in the world.
Francis has twice received President Vladimir Putin at the Vatican since he was elected pope in 2013.
"In the background there is a third player (Putin)," Vatican expert Marco Politi wrote in a blog on the historic encounter.
"It would be naive to believe the sudden availability of the Patriarch is unrelated to the geopolitical situation Russia finds itself in at the moment," he argued, in a reference to Russia's intervention in Syria.
A spokesman for the Orthodox church in Moscow said he could "100 percent guarantee" that there was no political agenda behind the two religious leaders' meeting.
Alexander Volkov said he hoped the meeting would open the door to "new prospects of mutual cooperation," but emphasised that reunification of the Eastern and Western churches was not on the agenda.
Despite the breakthrough of a face-to-face meeting, Vatican-Orthodox relations remain strained.
The issues that caused the schism in the first place are unresolved and there are tensions over the perceived evangelism of the Catholic Church in Eastern Europe.
Then there is the fallout from the conflict in Ukraine, which has pitted Ukrainian Catholics loyal to Rome against separatists who are mostly Russian Orthodox.
Francis's arrival in Mexico on Friday evening is set to be a luminous affair, with hundreds of thousands of well-wishers expected to line the 12-mile (19-kilometre) route from the airport to the Vatican ambassador's residence in Mexico City.
The plan is for believers to light up the road Francis's popemobile will travel with their mobile phones or hand-held torches, creating what local organiser Roberto Delgado described as a "wall of light and prayer."
Francis will spend his nights in Mexico at the ambassador's residence in the capital, but will make a series of trips to outlying states stricken by violence and poverty.
To underline his commitment to the plight of migrants fleeing persecution and poverty in search of a better life, his schedule will take in trips to both the southern and northern borders.
His arrival in a country that is home to the second-largest Catholic community in the world (after Brazil) comes a day after a prison riot left 49 inmates dead in the north of the country.
He is also due to visit three places notorious for drug cartel mayhem: Ecatepec in Mexico State, Morelia in Michoacan and Ciudad Juarez in Chihuahua.
At Ciudad Juarez, located on the border with the United States, he will deliver an open-air mass which believers on the other side of the border, close to the Texas town of El Paso, will also be able to follow.
The cross-border service on Wednesday is expected to be one of the high points of the trip, but Francis has said the most emotional moment for him will come with Saturday's visit to the Basilica of our Lady of Guadalupe in Mexico City.
The sanctuary dedicated to the Virgin Mary is one of the most visited Catholic shrines in the world. Francis has visited twice prior to becoming pope and his schedule has been cleared for Saturday evening to allow him as much time as he wants for private prayer before the revered icon of the "Morenita" (the brunette virgin).