Hillary Clinton has arrived in Laos, the first US secretary of state to visit the country in 57 years.
She is expected to discuss plans to build a controversial Mekong River dam, which critics say would impact the environment and millions of lives.
The effects of Agent Orange, a defoliant used during the Vietnam war, are also likely to be on the agenda.
Mrs Clinton, who arrives in Vientiane from Vietnam, will then head to Cambodia for an Asean meeting.
The last top US diplomat to visit Laos was John Foster Dulles in 1955.
The $3.8bn (£650m) hydro-electric dam project at Xayaburi has caused tension among Mekong region countries - Laos, Vietnam, Cambodia and Thailand.
In April, a multi-billion dollar contract was signed for a Thai company, CH Karnchang, to build the dam.
The Lao government has pledged not to go ahead with the project until environmental issues have been resolved.
However, activists say work on the project has already begun, with reports and photographs emerging of construction vehicles in the area.
'Pivot toward Asia'
Mrs Clinton's trip is part of a tour of Asia which analysts say signals the United States' growing interest in the region.
"My trip reflects a strategic priority of American foreign policy today," she told reporters in Mongolia earlier this week.
"After 10 years in which we focused a great deal of attention on the conflicts in Afghanistan and Iraq, the United States is making substantially increased investments - diplomatic, economic, strategic and otherwise - in this part of the world. It's what we call our pivot toward Asia."
At the Asean regional forum later this week in the Cambodian capital, where she will join counterparts from the 10-nation bloc and other Asian countries, including China, tension in the South China Sea is expected to top the agenda.
She had earlier urged progress on a code of conduct for resolving conflict in the disputed waters between China and several South East Asian nations.