Although HIV prevention research has accomplished much over the last 2 decades, significant challenges remain. The accomplishments have included rapid progression through various stages of research--from descriptive to clinical trials--and the fielding of several Phase 3 trials with biological endpoints. The challenges include developing strategies and studies in the policy and structural arena. The authors outline 7 HIV policy and structural research challenges, with specific research questions, that will be critically important as researchers move forward to address the next 10 to 20 years of the epidemic without the benefit of prophylactic vaccines against HIV-1.