PURPOSE OF REVIEW: Remarkable advances in the use of antiretroviral medication in the prevention of HIV acquisition are receiving well deserved widespread attention. The behavioral and social-cultural factors that contextualize use of study product or preexposure prophylaxis (PrEP) are comparatively poorly understood. Given that PrEP is a bio-behavioral intervention, optimizing the potential impact of PrEP on individual and public health requires a better understanding of the behavioral aspects of PrEP adherence. This review culls across available clinical trial findings to suggest a behavioral agenda for research and practice. RECENT FINDINGS: Product use differs dramatically both within and between recent PrEP trials; however, numerous issues with measuring use have emerged. Factors influencing use or adherence are not well identified and continue to focus on the individual and discrete correlates. Presently, execution and cyclical use of open-label PrEP is unknown but is under investigation in a number of demonstration and open-label projects. SUMMARY: Research to identify methods for assessing product and PrEP use, factors influencing individual and community-level PrEP uptake and use, development of comprehensive models of protection of sexual health via multiple strategies now available, and strategies to best support adherence to dosing and HIV-testing requirements are identified as critical in a behavioral research agenda.