A key component of the shift from an emergency to a long-term response to AIDS is a change in focus from HIV prevention interventions focused on individuals to a comprehensive strategy in which social/structural approaches are core elements. Such approaches aim to modify social conditions by addressing key drivers of HIV vulnerability that affect the ability of individuals to protect themselves and others from HIV. The development and implementation of evidence-based social/structural interventions have been hampered by both scientific and political obstacles that have not been fully explored or redressed. This paper provides a framework, examples, and some guidance for how to conceptualise, operationalise, measure, and evaluate complex social/structural approaches to HIV prevention to help situate them more concretely in a long-term strategy to end AIDS.