US President Barack Obama says President Hosni Mubarak has answered Egypt's hunger for change.
Mr Mubarak has handed power to the military and left the capital.
At the White House on Friday, Mr Obama warned of difficult days ahead.
He called on the Egyptian military to end an oppressive emergency law, revise the constitution and begin preparing for free and fair elections.
Mr Obama said Egyptians had made it clear they wanted nothing less than genuine democracy.
The people of Egypt have spoken, their voices have been heard, he said. Egypt will never be the same again.
He praised the Egyptian military, saying they had served patriotically and responsibly.
In addition, Mr Obama called on the new military government to protect the rights of Egyptian citizens, rewrite the legal code to make the movement toward democracy irreversible and to lay out a clear path to fair and free elections.
Earlier, US Vice President Joe Biden hailed Mr Mubarak's exit from power on Friday as a pivotal moment for the Middle East.
He insisted Egypt's democratic transition must be irreversible.
The transition that's taking place must be an irreversible change and a negotiated path toward democracy, he said after Mr Mubarak handed over power to the military.
What is at stake in Egypt and across the Middle East is not just about Egypt alone, he said.
This is a pivotal moment in history, Mr Biden said. It's a pivotal moment not only in Mideast history, but in history.
US officials have said repeatedly they are entering uncharted waters and see a long period of uncertainty and volatility.
The Egyptian military receives $US1.3 billion in US aid annually.
Mohamed Hussein Tantawi, the head of the military junta, spoke to US Defence Secretary Robert Gates by phone five times during the wave of mass protest, including as Friday.
A senior Israeli official expressed the hope that Mr Mubarak's departure would bring no change to its peaceful relations with Cairo.
European Union leaders reacted positively to the news. Foreign policy chief Baroness Ashton said the EU respected the decision.
British Prime Minister David Cameron called for a move to civilian and democratic rule.
German Chancellor Angela Merkel welcomed the historic change in Egypt.
She said she expected Egypt's future government to continue to keep the peace in the Middle East, ensuring the agreements made with Israel are respected and Israel's security is guaranteed.
The Australian Foreign Affairs Minister, Kevin Rudd, has hailed the news as historic but says questions remain about Egypt's path to democracy.
UN Secretary-General Ban Ki-moon called on Friday for a transparent, orderly and peaceful transition, saying he wanted to see free, fair and credible elections that would lead to the early establishment of civilian rule.
Meanwhile, the Swiss government has frozen what it calls possible Mubarak assets in Switzerland.