But Francis' trip to Jordan, the West Bank and Israel has already been overshadowed by controversy over plans to celebrate Mass in a location revered by Orthodox Jews. Religious extremists were blamed for spray-painting the walls of churches and monasteries in Israel with vitriolic graffiti that included "Death to Christians" and "We will crucify you."
The attacks were roundly condemned by Catholics and Jews. Zion Evrony, Israel's ambassador to the Holy See, immediately responded by describing Francis as "a friend of the Jewish people" and stressing that the attacks were isolated.
"They were condemned by political and religious leaders," Evrony said. "They do not represent the policy of the government or the opinions or sentiments of the majority of Israelis. Israel respects and protects religious freedoms."
To be sure, in a region torn by centuries of political and religious conflict, there are plenty of challenges.
The Rev. David Neuhaus from the St. James Vicariate for Hebrew-speaking Catholics in Israel said the pope is sending a powerful message not only about dialogue and collaboration, but also "sharing dreams."
"These possibilities need to be underlined for those of us in the Middle East who are so used to the present realities of fighting, bad-mouthing, competition and negativity," Neuhaus said from Jerusalem.
Skorka is rector of the Latin American Rabbinical Seminary, and Abboud is president of the Institute for Interreligious Dialogue in Buenos Aires. Francis knows both men from his days as Cardinal Jorge Bergoglio of Buenos Aires.
"Francis' friendship with Skorka and Abboud will hopefully raise questions about our assumptions," Neuhaus said, "and allow us to imagine a world where different relations can be born."
This is the pope's second foreign trip since he assumed office in 2013 after his highly successful visit to Brazil last summer and it is certain to present the greatest test of his political and personal leadership to date.
When Pope John Paul II visited Israel in 2000, he prayed at the Western Wall and apologized to the Jews. Pope Benedict XVI provoked fury in 2009 when he remembered the "millions" killed during the Holocaust without specifying the precise number of 6 million Jewish victims on a visit to the Holocaust memorial Yad Vashem.
Francis has already stressed the "strictly religious" importance of this trip, which marks the 50th anniversary of the historic meeting between Pope Paul VI and the spiritual leader of Eastern Orthodoxy, Ecumenical Patriarch Athenagorus.
That 1964 visit was the first step in overcoming 1,000 years of bitter conflict between the two oldest branches of Christianity, although the two churches are not yet in full communion with each other.
Francis is scheduled to meet with the current Ecumenical Patriarch, Bartholomew I, who represents 230 million Orthodox Christians, on four occasions during this trip. The two men will sign a joint declaration despite opposition from some Orthodox leaders.
"It's clear that this visit cannot resolve all the problems of the dialogue of truth, but it will deepen the friendship and the brotherhood, the fraternal relations," Cardinal Kurt Koch, who heads the Pontifical Council for Promoting Christian Unity, told Vatican Radio.
The three-day visit is packed with official appointments and a grueling physical schedule for the 77-year-old pontiff.
In Jordan, he will meet with King Abdullah II and Queen Rania and celebrate Mass in an Amman stadium, where 1,400 children will receive Communion for the first time. In Bethlehem, a meeting is scheduled with the Palestinian leader, Mahmoud Abbas, and refugee children.
The pope's plan to celebrate Mass in the Cenacle, the room where Christ is believed to have celebrated the Last Supper, angered Orthodox Jews, who also revere the site as the tomb of King David. Some Palestinian officials had hoped the pope would use his trip to Bethlehem to recognize Palestine.
But that seems highly unlikely after it was revealed that Francis would visit the tomb of Zionist pioneer Theodor Herzl, seen by many as a gesture apologizing for the Vatican's initial opposition to Jewish self-determination.
When he flies to Israel, Francis will meet with Israeli President Shimon Peres and Prime Minister Benjamin Netanyahu as well as local rabbis. Like his predecessors, Francis will visit the Western Wall and Yad Vashem.
It's clear that the pope has the power and popularity to set a new tone in the Middle East, but one veteran Vatican watcher has already warned that may not be enough to bring about real change.
"The pope has shown himself to be an extraordinary leader, but he is not a miracle worker," said the Rev. Tom Reese, a well-known Jesuit author and analyst in Washington. "The pope constantly surprises us, leads us to hope, but experience warns us to be realistic."