Men who have sex with men, including transgender women, comprise a heterogeneous group of individuals, whose sexual behaviors and gender identities may varying widely between cultures and among individuals. Their sources of increased vulnerability to HIV are diverse, including the increased efficiency of HIV transmission via unprotected anal intercourse, sexual role versatility, asymptomatic sexually transmitted infections, as well as behavioral factors that may be associated with condomless sex with multiple partners. Societal stigmatization of homosexual behavior and gender non-conformity may result in internalized negative feelings that lead to depression, other affective disorders, and substance use, which in turn are associated with increased risk taking behaviors. Social stigma and punitive civil environments may lead to delays in seeking HIV and STD screening, and later initiation of antiretroviral therapy. The iPrEX study demonstrated that chemoprophylaxis can decrease HIV acquisition in MSM, and the HPTN 052 study established the biological plausibility that earlier initiation of HAART can decrease HIV transmission to uninfected partners. Despite these advances, MSM remain among the most significantly HIV-affected population in resource rich and limited settings. New studies will integrate enhanced understanding of the biology of enhanced rectal transmission of HIV and the focused use of antiretrovirals for prevention with culturally-tailored approaches that address the potentiating social and behavioral factors associated with enhanced HIV spread among MSM.