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In the United States, substance abuse and the acquired immunodeficiency syndrome (AIDS) epidemic are closely linked. This, article explores the complexity and diversity of the different populations affected by the AIDS epidemic and the consequent challenges presented to researchers and clinicians who design intervention strategies. Because human immunodeficiency virus (HIV) transmission occurs by means of high-risk behaviors programs designed to modify behaviors to prevent the further spread of the virus are of paramount importance. In an attempt to address some of the unique needs of high-risk populations, specific groups are considered, including women, adolescents, the mentally ill drug users and homeless individuals. The successful reduction or prevention of HIV transmission hinges on tailoring messages to target populations in a meaningful manner that takes into account the unique needs of those who are at risk.