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Previous papers in this supplement have reviewed the evidence of the effectiveness of alternative HIV prevention methods from randomized controlled trials and other studies. This paper draws together the main conclusions from these reviews. A conceptual framework is presented that maps the proximal and distal determinants of sexual HIV transmission and helps to identify the stages in the causal pathway at which each intervention approach acts. The advances, gaps and challenges emerging from the reviews of individual intervention methods are summarized and cross-cutting themes identified. Approximately 90% of HIV prevention trials have found no effect on HIV incidence and we explore the alternative explanations for the large number of ‘flat’ trials. We conclude that there is no single explanation for these flat results, which may be due to interventions that are ineffective or inappropriately targeted or implemented, or to factors related to the design or conduct of trials. We examine the lessons from these flat results and provide recommendations on what should be done differently in future trials. HIV prevention remains of critical importance in an era of expanded delivery of antiretroviral therapy. In future HIV prevention research, it is important that resources are used as efficiently as possible to provide rigorous evidence of the effectiveness of a wider array of complementary prevention tools.