Africa carries a disproportionate burden of the global HIV endemic, accounting for two thirds of the global 33.3 million people living with HIV. While tremendous advances have been made in addressing the HIV epidemic in Africa, considerable challenges remain. Testing for HIV increased by 86% from 2007 to 2009 but more than 75% of people 15-49 years remain unaware of their HIV status. CD4 count at diagnosis tends to be low and linkage to care and treatment is suboptimal. The scale-up of antiretroviral therapy is ongoing but is hampered by the lack of diagnostic capability to monitor response to therapy and a substantial healthcare workforce shortage. Prevention strategies such as male circumcision, pre-exposure prophylaxis, and antiretroviral therapy for prevention have generated great excitement but cost and healthcare infrastructure deficiencies may limit their widespread applicability. Operational research to validate and inform treatment decisions, health care policies, and prevention strategies is sorely needed.