The convergence of HIV, substance abuse (SA), and mental illness (MI) represents a distinctive challenge to health care providers, policy makers, and researchers. Previous research with the mentally ill and substance-abusing populations has demonstrated high rates of psychiatric and general medical comorbidity. Additionally, persons living with HIV/AIDS have dramatically elevated rates of MI and other physical comorbidities. This pattern of co-occurring conditions has been described as a syndemic. Syndemic health problems occur when linked health problems involving 2 or more afflictions interact synergistically and contribute to the excess burden of disease in a population. Evidence for syndemics arises when health-related problems cluster by person, place, or time. This article describes a research agenda for beginning to understand the complex relations among MI, SA, and HIV and outlines a research agenda for the Social and Behavioral Science Research Network in these areas.