Context: The rural Black Belt of Alabama is among the poorest areas of the nation. Poverty, lack of health infrastructure, and health disparities involving HIV/AIDS and other diseases reflect the lower life expectancy of people in the region. The Black Belt region has the highest HIV rates in rural America. Purpose: Using Alabama as a case example, the paper describes the role of illicit drug use in pathways to HIV transmission in the Black Belt and examines the relationship between drug use and social context with respect to HIV/AIDS disparities in the region. Methods: Published research and national and state data were triangulated for information on interactions between illicit drug use, social context, and HIV/AIDS. Findings: Illicit drug use is implicated in HIV risk in Alabama's Black Belt, but less so than in other parts of the nation. Published research suggests that the impetus for drug use involves status seeking in the context of heterosexual contact and economic disparities. HIV transmission in Alabama's Black Belt speaks to the tyranny of small places; that is, the risk of HIV/AIDS occurs in geographically bounded areas with a history of racial homogeneity, historically high rates of sexually transmitted infections, and clustered sexual networks in this isolated region. Conclusions: Social context is an important correlate of HIV risk in the Black Belt. The role of drug use in HIV risk is secondary to social-contextual factors involving rural isolation, racial homogeneity, and the racial disparities of the region.