: Pre-exposure prophylaxis (PrEP) is a potent and underutilized HIV prevention tool. In this paper we review the state of knowledge regarding PrEP implementation for men who have sex with men and transgender persons in early adopting countries. We focus on implementation of PrEP in demonstration projects and clinical care, and describe the status of PrEP availability and uptake. We report on approaches to identifying appropriate PrEP candidates in real-world settings and on best practices for clinical monitoring. This includes the exclusion of undiagnosed HIV infection prior to PrEP initiation and longitudinal measurement of renal function, in light of safety data. Since adherence is the primary factor moderating the effectiveness of PrEP, we discuss effective adherence support interventions. Additionally, we review the evidence for risk compensation with PrEP use and opportunities to provide PrEP as part of comprehensive and inclusive preventive health programs. We summarize cost-effectiveness studies, including their variable conclusions because of differing underlying assumptions, and discuss the importance of budgetary impact for public health programs and health care insurers. Further, we emphasize a need for greater engagement of health care providers in PrEP to increase access. We conclude with recommendations for ways to improve future efforts at implementing PrEP.