Evidence-informed and human rights-based combination prevention combines behavioural, biomedical, and structural interventions to address both the immediate risks and underlying causes of vulnerability to HIV infection, and the pathways that link them. Because these are context-specific, no single prescription or standard package will apply universally. Anchored in ‘know your epidemic’ estimates of where the next 1000 infections will occur and ‘know your response’ analyses of resource allocation and programming gaps, combination prevention strategies seek to realign programme priorities for maximum effect to reduce epidemic reproductive rates at local, regional, and national levels. Effective prevention means tailoring programmes to local epidemics and ensuring that components are delivered with the intensity, quality, and scale necessary to achieve intended effects. Structural interventions, addressing the social, economic, cultural, and legal constraints that create HIV risk environments and undermine the agency of individuals to protect themselves and others, are also public goods in their own right. Applying the principles of combination prevention systematically and consistently in HIV programme planning, with due attention to context, can increase HIV programme effectiveness. Better outcome and impact measurement using multiple methods and data triangulation can build the evidence base on synergies between the components of combination prevention at individual, group, and societal levels, facilitating iterative knowledge translation within and among programmes.