Sub-Saharan Africa is the region affected worst by human immunodeficiency virus (HIV), with the most southern countries, including Botswana, Zimbabwe, Swaziland, and South Africa, carrying the highest disease burden. This geographic distribution represents a complex interaction among virological, political, social, cultural, and economic forces. In South Africa the HIV epidemic is seemingly unchecked, with 18% of the adult population infected. Although South Africa is a mid-developed country, there is a large chasm between the wealthy and the poor, with many living in moderate to extreme poverty. Poverty creates conditions that fuel the HIV epidemic while HIV exacerbates the multiple interlinking causes of poverty. Children are the most vulnerable members of society, severely affected by all components of the poverty cycle. Although improved health education and access to care will alleviate many problems, sustainable poverty alleviation should form an essential component of the response to AIDS. The formulation of the United Nations Millennium Developmental Goals is an important step in the right direction, but global and local political commitment is essential for success.