Transgender communities are among the groups at highest risk for HIV infection in the United States. Using syndemic theory, we examine how HIV risk in transgender communities is embedded in multiple co-occurring public health problems, including poor mental health, substance use, violence and victimization, discrimination, and economic hardship. Although safer sex counseling and testing programs are essential platforms for HIV intervention, these modalities alone may be insufficient in reducing new infections. Multicomponent interventions are necessary to respond to the complex interacting syndemic factors that cumulatively determine HIV vulnerability in transgender individuals.