HIV is a public health crisis that disproportionately affects Black and Latino men. To understand this crisis, syndemic theory, which takes into account multiple interrelated epidemics, should be used. A syndemic is "two or more afflictions, interacting synergistically, contributing to excess burden of disease in a population." Vulnerability to HIV among Black and Latino men is increased as structural, social, and biological factors interact in the context of social marginalization. In New York City, Black and Latino men experience a syndemic of HIV/AIDS, substance abuse, trauma, incarceration, and poverty; however, current research has yet to fully identify the mechanisms of resilience that may reduce the negative impact of a syndemic or explore the potential adaptive functions of individual-level risk behaviors. To understand HIV risk as part of a syndemic and address HIV prevention in Black and Latino men, we propose the following: (1) the use of complex systems analysis, ethnography, and other mixed-methods approaches to observe changes in relations among social conditions and disease; (2) multidisciplinary and inter-institution collaboration; and (3) involvement of public health practitioners and researchers from diverse and underrepresented backgrounds.