The U.S. HIV/AIDS epidemic has evolved over the past 30 years and is now concentrated in socially marginalized and disenfranchised communities. The health disparities in this epidemic are striking, with most HIV infections occurring in sexual minorities and communities of color. While widely recognized, the health disparities in HIV and AIDS are not often discussed. In this article, we examine the factors underlying health disparities in the U.S. HIV epidemic. We first discuss the interlocking relationships between biological, social, and behavioral factors that drive HIV/AIDS epidemics. Guided by a well-established conceptual model of health disparities, we then describe the social positions of those most affected by HIV and AIDS, particularly racial and gender groups. Structural and economic conditions-including environmental resources, constraints, access to care, and psychosocial influences-are examined in relation to HIV disease trajectories. Greater attention to contextual factors and comorbidities is needed to reduce the health disparities in HIV/AIDS.