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This article provides an overview of a growing body of international research focusing on the structural and environmental factors that shape the spread of the HIV/AIDS epidemic, and create barriers and facilitators in relation to HIV-prevention programs.Most of the research on structural and environmental factors can be grouped into a small number of analytically distinct but interconnected categories: economic (under)development and poverty; mobility, including migration, seasonal work, and social disruption due to war and political instability; and gender inequalities. An additional focus in research on structural and environmental factors has been on the effects of particular governmental and intergovernmental policies in increasing or diminishing HIV vulnerability and transmission.A smaller subset of the research on structural factors describes and/or evaluates specific interventions in detail. Approaches that have received significant attention include targeted interventions developed for heterosexual women, female commercial sex workers, male truck drivers, and men who have sex with men.The structural and environmental factors literature offers important insights and reveals a number of productive intervention strategies that might be explored in both resource-rich and -poor settings. However, new methodologies are required to document and evaluate the effects of the structural interventions, which by their very nature involve large-scale elements that cannot be easily controlled by experimental or quasi-experimental research designs. Innovative, interdisciplinary approaches are needed that can move beyond the limited successes of traditional behavioral interventions and explicitly attempt to achieve broader social and structural change.