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Four of the largest HIV prevention trials have been conducted in sub-Saharan Africa, enrolling hundreds of thousands of participants in catchment areas of millions of people. The trials have focused on community-level interventions to increase diagnosis and initiation of antiretroviral therapy (ART) to improve health and reduce HIV transmission. Universal test-and-treat strategies are deployed to achieve viral suppression thereby reducing risk to uninfected persons, known as treatment as prevention (TasP).We review the work that found HIV plasma load to correlate with transmission risk, demonstrated that ART could reduce genital tract viral expression, and showed early treatment to be beneficial for persons living with HIV, and that HIV-uninfected sexual partners were protected from infection. We review the seemingly inconsistent findings of the major TasP trials: the TasP [National Agency for AIDS Research (ANRS) 12249] study in South Africa, the SEARCH trial in Kenya and Uganda, the Botswana Combination Prevention Project Ya Tsie study, and the HIV Prevention Trials Network 071 (PopART) trial in Zambia and South Africa.All the trials reinforce the critical need to identify approaches to optimize programs and incentivize uptake and engagement in HIV testing and ART-based care in ways that consistently reduce HIV transmission. That other chronic conditions can be screened for and treated in the same infrastructures suggests added value of HIV investments.Implementation challenges are a principal frontier in the global struggle to reduce HIV transmission and mortality using TasP, complementing efforts to find a cure for HIV and an effective, deployable vaccine.