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Substantial progress has been made in reducing HIV among injection drug users (IDUs) in the United States, despite political and social resistance that reduced resources and restricted access to services. The record for HIV prevention among noninjecting drug users is less developed, although they are more numerous than IDUs. Newer treatments for opiate and alcohol abuse can now be integrated into primary HIV care; treatment for stimulant abuse is less developed. All drug users present challenges for newer HIV prevention strategies (eg, “test and treat,” nonoccupational postexposure prophylaxis and preexposure prophylaxis, contingency management, and conditional cash transfer). A comprehensive HIV prevention program that includes multicomponent multilevel approaches (ie, individual, network, structural) has been effective in HIV prevention among IDUs. Expanding these approaches to noninjecting drug users, especially those at highest risk (eg, minority men who have sex with men) and incorporating these newer approaches is a public health priority.