This article examines the epidemiology of HIV among selected subgroups of drug users around the world who are "most at risk"--men who have sex with men, female sex workers, prisoners, and mobile populations. The underlying determinants of HIV infection among these populations include stigma, physical and sexual violence, mental illness, social marginalization, and economic vulnerability. HIV interventions must reach beyond specific risk groups and individuals to address the micro-level and macro-level determinants that shape their risk environments. Public health interventions that focus on the physical, social, and health policy environments that influence HIV risk-taking in various settings are significantly more likely to impact the incidence of HIV and other blood-borne and sexually transmitted infections across larger population groups.