Over the past 3 years, significant strides have been made in the effort to provide antiretroviral therapy (ART) to the millions of people worldwide who require treatment for HIV. In 2006, 1.3 million people had initiated ART in sub-Saharan Africa, which is a 10-fold increase over the number who had access to treatment 3 years prior. Although this progress should be acknowledged, achieving universal access will require much more work. As countries initiate large-scale treatment programs, many political, social, economic, and operational challenges have become evident. South Africa, Zimbabwe, and Botswana are three neighboring countries engaged in ART roll-out. This article describes the HIV epidemic in these three countries, details the most critical challenges inhibiting the progression of antiretroviral therapy rollout, and highlights successes within each setting.