After 30 years of extensive research on human immunodeficiency virus (HIV) among persons who inject drugs (PWID), we now have a good understanding of the critical issues involved. Following the discovery of HIV in 1981, epidemics among PWID were noted in many countries, and consensus recommendations for interventions for reducing injection related HIV transmission have been developed. While high-income countries have continued to develop and implement new Harm Reduction programs, most low-/middle-income countries have implemented Harm Reduction at very low levels. Modeling of combined prevention programming including needle exchange (NSP) and antiretroviral therapy (ARV) suggests that NSP be given the highest priority. Future HIV prevention programming should continue to provide Harm Reduction programs for PWID coupled with interventions aimed at reducing sexual transmission. As HIV continues to spread in low- and middle-income countries, it is important to achieve and maintain high coverage of Harm Reduction programs in these locations. As PWID almost always experience multiple health problems, it will be important to address these multiple problems within a comprehensive approach grounded in a human rights perspective.