Over the past 20 years, tremendous strides have been achieved in the response to HIV/AIDS, especially in the incredible scale-up of life-saving ART to over 25 million people globally, most of them in Africa. This heroic achievement has resulted in an estimated 56% reduction in mortality since 2004 and as a consequence led to an increasing life expectancy and a marked drop in HIV/AIDS orphans – all of which are significant population impacts. However, the expected reductions in new infections have only been achieved modestly with an estimated reduction of HIV incidence of 16% in the 10 years since 2010. This is in part due to the challenge of translating scientifically proven HIV prevention interventions like ART, PMTCT, and VMMC and PreP into an environment that has many obstacles and challenges that include funding constraints, struggling health systems, disempowered communities and structural barriers. In particular, HIV prevention faces the challenge of promoting approaches like condoms that often face opposition from some politicians, cultural leaders, and religious leaders. Other approaches like VMMC and PreP face both opposition and skepticism, on the grounds that there are fears that individuals using these partially effective approaches will exhibit a rebound increase in risky sexual behaviors that will lead to new HIV infections. In addition, many of the target populations that are at greatest risk for HIV infection are also the groups that are the hardest to reach because they are considered illegal, are harassed and discriminated and often live and operate underground to avoid scrutiny. However, there are several excellent examples of effective scale-up of scientifically proven interventions and population impact, as well as a few examples of large scale combination HIV treatment/prevention interventions that have reduced HIV incidence at a population level. These examples provide hope and a template to use when planning to scale up new technologies like PreP, as well as scaling up the use of older technologies like condoms. However for this to be successful at the frontline it will require scientists and politicians and communities and frontline implementers to sit down together, listen to each other, understand the science AND the realities of people’s lives and the systems that support them, and come up with scientifically sound and pragmatic approaches to scale up services, impact populations and measure progress. The history of HIV has many lessons for us as we look into the future. Science, even brilliant science, will not end the HIV epidemic without collaboration and synergy with a wide range of other actors, strategies and full involvement of infected and affected communities.