Here are highlights on the schedule for President Donald Trump's first overseas trip in office.
"Can he move forward with his own agenda?" While in Saudi Arabia, Trump is scheduled to give a speech in support of moderate Islam. Also on the agenda: the North Atlantic Treaty Organisation leaders' meeting and dinner, with Defense Secretary Jim Mattis.
"It's nearly always true that when a president goes on a big foreign trip, especially one that has some important summits. that that dominates the news and knocks most other stuff out", said Republican strategist Charlie Black.
Trump has backed away from a decades-old USA commitment to a sovereign Palestinian state, but held a warm meeting at the White House with Palestinian President Mahmoud Abbas.
The White House laid out three purposes for the trip: reaffirming US leadership globally, building relationships with world leaders and broadcasting "a message of unity to America's friends and to the faithful of three of the world's greatest religions", said national security adviser H.R. McMaster.
In Trump, many Saudis see a decisive, business-focused leader, who they say shares their goals in the region.
"If Trump were really honouring his campaign commitments to the American workers, he would be going to Mexico or China to do something for the economy, jobs and trade", Hoh, a scholar at Center for International Policy, a left-wing think tank, told MEE.
Iran election: Jahangiri quits, backs Rouhani
Iranian media have discussed him as a potential future successor to Khamenei, who turns 78 in July. Raisi has promised a return to the values of the 1979 Islamic Revolution.
"What we don't know is which of these, the more intense solidarity Donald Trump or the more skeptical Donald Trump we're going to see", said Stephen Sestanovich, who was an ambassador at large for the former Soviet Union from 1997 to 2001.
Trump's advisers saw it as an opportunity for the United States to boldly reassert itself on the world stage and resume a leadership role that the administration believes was abdicated by President Barack Obama.
He said Iran would retaliate by adding nine United States individuals and companies to its own sanctions list, accusing them of "clear violations of human rights" in relation to their support for Israel or "terrorist groups" in the Middle East.
The third summit will be between Trump and the heads of state and leaders of Arab and Islamic states members of the Islamic Alliance to combat terrorism.
Saudi Arabia recognizes that economic interdependence is key. Trump has also decided not to announce during his trip that he will move the U.S. embassy from Tel Aviv to Jerusalem, as he vowed to do during the campaign. "We look at actions", said Al-Jubeir, repeating allegations about Iran's "aggressive" behavior in the Middle East.
That seems a long-shot anyway.
Trump will meet with the presidents of the European Union and the European Council at the EU's headquarters in Brussels, McMaster said. The president will then travel to Israel and the Vatican, before attending a North Atlantic Treaty Organisation leaders meeting in Brussels and a G7 summit in Sicily.