PURPOSE OF REVIEW: The aim of this article is to outline key challenges facing the conduct of efficacy trials for biomedical strategies to prevent HIV infection. RECENT FINDINGS: The past 2-3 years have seen tumultuous development in this field. There have been disappointing findings in efficacy trials of vaginal microbicides, vaccines, the diaphragm and suppressive therapy for herpes, but a major breakthrough with the evidence that male circumcision prevents acquisition of infection. Meanwhile, clarity has started to emerge on a number of issues regarding trial conduct, including provision of standard of care, involvement of communities, and preparation for implementing effective interventions. SUMMARY: HIV prevention practice must continue to rely on condom promotion and other established strategies while biomedical approaches continue to be assessed and their implementation strategies evolve.