Gay, bisexual, and other men who have sex with men (MSM) have been disproportionately affected by HIV and AIDS since the beginning of the epidemic in the United States and in many other parts of the world. The HIV epidemic is inextricably tied to other health problems that disproportionately affect gay, bisexual, and other MSM including psychological comorbidities, substance use, sexual victimization, stigmatization, and multiple forms of discrimination. These interrelated health problems and social issues can be characterized as a syndemic of mutually reinforcing conditions or epidemics. Moreover, the syndemic is directed by biological, behavioral, psychosocial, and structural determinants. Addressing HIV within the context of a larger syndemic will require a more holistic approach to HIV prevention and treatment that recognizes the interplay between biological, behavioral, psychosocial, and structural factors that affect the health and well-being of sexual minority men.