Homelessness and housing instability are significant public health issues that increase the risks of HIV acquisition and transmission and adversely affect the health of people living with HIV. This article highlights the contributions of selected papers in this special issue of AIDS and Behavior and considers them within the broader context of prior research on the associations between housing status and HIV risk, use of HIV medical care, adherence to HIV treatment, and the physical health of HIV-seropositive persons. Special recognition is given to the roles of interrelated health problems, such as substance abuse, poor mental health, and physical and sexual abuse, that often co-occur and exacerbate the challenges faced by those who are homeless or unstably housed. Taken as a whole, the findings indicate a critical need for public health programs to develop strategies that address the fundamental causes of HIV risk among homeless and unstably housed persons and, for those living with HIV, contribute to their risk of disease progression. Such strategies should include "mid-stream" and "upstream" approaches that address the underlying causes of these risks. The successful implementation of these strategies will require leadership and the formation of new partnerships on the part of public health agencies. Such efforts, however, may have significant effects on the individuals and communities most affected by HIV/AIDS.