Opportunistic infections (OIs) were first recognized among injection drug users (IDUs) in New York City in 1981. By the mid-1980s, OIs had become associated with HIV infection, and attention began to focus on efforts to prevent HIV transmission among IDUs. Since then, a range of prevention strategies has been implemented and evaluated in an attempt to reduce the spread of HIV infection among drug users. These prevention strategies include (1) HIV testing and counseling and educational and behavioral interventions delivered through community outreach; (2) condom, bleach, and needle distribution and syringe access and exchange programs; (3) substance abuse treatment; and, more recently, (4) prevention interventions targeting HIV-positive IDUs. Data from evaluations of these strategies over the past 20 years have provided substantial evidence of effectiveness and have helped to inform network-based and structural interventions. Despite the cumulative empirical evidence, however, research findings have yet to be widely disseminated, adopted, and implemented in a sustained and integrated fashion. The reasons for this are unclear, but point to a need for improved communications with program developers and community planners to facilitate the implementation and evaluation of integrated intervention strategies, and for collaborative research to help understand policy, legal, economic, and local barriers to implementation.