Efforts to prevent HIV transmission among substance-using populations have focused primarily among injection drug users, which have produced measurable reductions in HIV incidence and prevalence. By contrast, the majority of substances used worldwide are administered by noninjectable means, and there is a dearth of HIV prevention interventions that target noninjecting substance users. Increased surveillance of trends in substance use, especially cocaine (including crack) and methamphetamine, in addition to new and emerging substances (eg, synthetic cannabinoids, cathinones, and other amphetamine analogs) are needed to develop and scale up effective and robust interventions for populations at risk for HIV transmission via sexual behaviors related to noninjection substance use. Strategies are needed that address unique challenges to HIV prevention for substance users who are HIV infected and those who are HIV uninfected and are at high risk. We propose a research agenda that prioritizes (1) combination HIV-prevention strategies in substance users; (2) behavioral HIV prevention programs that reduce sexual transmission behaviors in nontreatment seeking individuals; (3) medical and/or behavioral treatments for substance abuse that reduce/eliminate substance-related sexual transmission behaviors; and (4) structural interventions to reduce HIV incidence.