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He'll declare a clean break from the Bush administration's "war-on-terror" approach to foreign affairs and forcefully endorse establishing a Palestinian state.
He'll talk about his respect for Islamic culture and call for an era of partnering with Muslim nations in areas of common interest, including curbing extremists before they destabilize Muslim nations and threaten the West.
Having publicly demanded that Israel stop building settlements in the largely Palestinian West Bank, he'll also ask Arab nations to recognize Israel's existence.
Tying together all the elements of such a speech is no easy proposition, for his worldwide audience - Muslim and non-Muslim - reflects competing priorities.
Lebanese go to the polls just three days after he speaks, Iranians will be preparing for pivotal elections June 12, and both contests pit moderate parties against radical forces.
Afghans and Pakistanis are girding for more U.S. military and political engagement.
Palestinians and Israelis have conflicting stakes.
In the United States, Republicans will be looking for opportunities to paint the Democratic president as anti-Israel or soft on terrorism.
"No matter how broadly he speaks, what he says will be parsed through the lens of those disagreements," said Tamara Cofman Wittes, director of the Middle East Democracy and Development Project at the Brookings Institution's Saban Center for Middle East Policy.
Obama said he won't lay out details for resolving the Arab-Israeli crisis. "I want to use the occasion to deliver a broader message about how the United States can change for the better its relationship with the Muslim world," the president said Thursday.
Obama would like to rally Muslim countries to join in efforts to contain Iran's nuclear program. But while many Arab governments also see Iran as a threat, the issue divides Muslims, in part because Israel is pressing for military action.
The speech will fulfill, with about a month's delay, Obama's campaign promise to make a major address in a Muslim city in his first 100 days in office.
His choice of Egypt is symbolically important in terms of U.S. interests. It reached peace with Israel long ago, and it's been an ally against terrorist groups such as Hezbollah and in terms of seeking to contain Iran's power.
But many Egyptians fear their autocratic president, Hosni Mubarak, and polling by the Gallup organization finds that most Egyptians don't think that the United States is serious about promoting democracy in the region.
Muslims tell pollsters that one of the most important things Westerners can do to improve relations with them is to stop seeing them as inferior, said Dalia Mogahed, the Egyptian-born executive director of the Gallup Center for Muslim Studies and a member of the White House Advisory Council on Faith-Based and Neighborhood Partnerships, which provided input for Obama's speech.
"If I were to convey the three major themes that I think would be important to cover in the speech, they would be the idea of respect, cooperation, and a demonstration of empathy," she said.
White House aides have emphasized that Obama will gear his remarks in Cairo to the masses, more than to governments, and to all Muslims, not just Egyptians.
That worldwide audience includes Arabs, but also Muslims altogether removed from the region, living in places with different interpretations of Islam, such Indonesia, where Obama lived as a boy.
His speech will be compared to the address then-Secretary of State Condoleezza Rice made in Egypt in 2005, calling on Arab nations to become more democratic and for Egypt to lead the way.
The Bush administration's push for rapid democratization backfired, empowering radical groups such as Hamas and Hezbollah.
"I believe he is not going to say much about democratization and liberalization," said Amr Hamzawy, an Egyptian political scientist based at the Carnegie Endowment for International Peace.
Mogahed said Muslims consider Obama, the son of a black Muslim immigrant raised by his white single mother, "a testament to what people say they admire the most about the United States, which at the end of the day is meritocracy."
His audience will want details about the future, however. Will former Guantanamo detainees be tried in civilian or military courts? Will Obama use U.S. leverage to ensure that Israel doesn't attack Iran, to compel a halt to settlement construction, and to adopt a more humanitarian approach to Gaza?
"The speech just can't be only about culture and religion," Mogahed said.