Behavior change remains a cornerstone of effective HIV prevention, whether interventions aim to reduce primary HIV acquisition or in the context of ‘prevention for positives’, the likelihood of onward transmission. However, to optimize the growing number of biomedical interventions, both prevention and implementation science will need to take a broader view of what they consider to be behavior change, move away from a narrow focus on risk behaviors and give greater consideration to health-seeking behaviors, social practices, cultural and social norms. These have been largely excluded from primary prevention thinking in southern Africa. Exciting developments in other areas of HIV research science, for example viral genetics, molecular and spatial epidemiology, can also be part of this process as they are able to help us to identify sub-populations at greatest risk, even in severe generalized epidemics. A number of biomedical interventions are already being rolled out, and attempts to bring them to scale will peak in the next few years. Much needs to be done to support these efforts, but equally much can be learned from the challenges that can have wider value in other resource-poor contexts. With better understanding and more accurate targeting of sub-populations, communities and behaviors, it will be possible to strengthen biomedical intervention strategies and improve allocation of prevention resources.