President Barack Obama headed for China to on a trip that will focus on Washington's often tense relations with the country, and will also see the president visit Myanmar and Australia.
The China stop will be dominated by Obama's meeting with Chinese President Xi Jinping in Beijing, where the White House said it expects "candid and in-depth conversations."
The relationship between the two superpowers, which US Secretary of State John Kerry has called the "most consequential" in the world today, has been marred by tensions over the South China Sea, cyberspying and human rights issues.
Obama will also attend an Asia-Pacific Economic Cooperation (APEC) summit in Beijing.
The president boarded the flight for Beijing in grey slacks and a casual black windbreaker, accompanied by National Security Advisor Susan Rice and senior adviser Dan Pfeiffer, among others.
In Myanmar, Obama will meet President Thein Sein and opposition icon Aung San Suu Kyi and attend a summit of ASEAN nations in Naypyidaw.
Washington has raced to normalize ties with Myanmar following reforms there, removing most US sanctions imposed on the military junta.
But Suu Kyi warned this week that the pace of change was slowing, and that the US had been "over-optimistic about the reform process" at times.
The White House said it remained committed to democratic reform in Myanmar.
"We will underscore the United States' commitment to the protection of human rights, tolerance and pluralism, as well as sustaining and deepening the democratic transition," Rice said.
When the president goes on to a G20 summit in Brisbane, Australia, the unrest in Ukraine may also be a focus.
Obama could meet with his Russian counterpart Vladimir Putin to discuss Ukraine.
No formal meetings have been scheduled, but neither side has ruled out the possibility of informal discussions. The last time the two leaders met face to face was in June in France.
North Korea could also be on the agenda, following the arrival of two Americans in the US on Saturday following their release from prison, which Obama called "wonderful.
