Lesotho suffers from high infant mortality rates and levels of malnutrition, in addition to having a high prevalence of tuberculosis and HIV/AIDS. 

The vast majority of USAID’s work in Lesotho is related to the President’s Emergency Plan for AIDS Relief (PEPFAR) program. It is managed by USAID's Southern Africa Regional HIV/AIDS Program in Pretoria. Through the U.S.-Lesotho Partnership Framework on HIV and AIDS, the program focuses on the following four areas:

1. Reducing HIV incidence;
2. Reducing HIV/AIDS-related morbidity and mortality by providing treatment and care to people living with HIV and orphans and vulnerable children;
3. Improving human resource capacity to deliver HIV services; and
4. Strengthening health management information systems, labs, organizational capacity, and supply chains.

Other programs include a democracy and governance activity focusing on judicial independence and human rights, an economic growth activity that reduces obstacles to foreign investment and seeks to expand the textile and garment industry, a climate change initiative, and humanitarian assistance programs.