Comprehensive HIV prevention interventions are increasingly recognized as critical in the global effort to reduce HIV transmission among people who use injection drugs. Scientific evidence clearly shows that a variety of biomedical, behavioral, and structural interventions can prevent and reduce injection drug user-driven HIV epidemics, yet social and structural barriers to their implementation remain. This review discusses the scientific evidence on the effectiveness of individual programs for reducing HIV incidence among people who use injection drugs and how, by integrating individual programs as complements within a comprehensive HIV prevention approach, it is possible to achieve, and to sustain, greater results than those of individual programs alone. The article concludes with a discussion of a critical research priority; namely, to improve the implementation of comprehensive HIV prevention interventions in settings of prevalent injection drug use and to overcome the often complex barriers that impede them. Such an effort will require more than research alone, however. It will also require the ongoing commitment of policymakers, public health officials, and the affected communities themselves to use comprehensive HIV treatment and prevention as the most effective strategy to reduce new HIV infections.