Nearly 40,000 Americans are newly infected with Human Immunodeficiency Virus (HIV) each year. Recently, studies have demonstrated associations between group-level characteristics and the prevalence and incidence of HIV/Acquired Immune Deficiency Syndrome (AIDS) and other sexually transmitted diseases. Two mechanisms previously posited to explain these associations are neighborhood effects on risk behaviors and social or institutional policies. In this paper, we hypothesize that adversity at the population level, such as neighborhood poverty, also influences HIV risk through stress-mediated aberrations in immunological susceptibility by reviewing existing data examining each of these pathways. In particular, we review the evidence showing that: (1) Neighborhood ecologic stressors influence neighborhood- and individual-levels of mental health, psychosocial stress, and HIV/AIDS risk, (2) Individual-level psychosocial stressors influence progression from HIV to AIDS through stress-related hormonal changes, and (3) Individual-level psychosocial stressors influence HIV acquisition via stress-related reactivation of latent herpesviruses, specifically EBV and HSV-2. Our review indicates that further studies are needed to examine the joint pathways linking neighborhood-level sources of psychosocial stress, stress-related reactivation of HSV-2 and EBV, and increased acquisition rates of HIV. We suggest using a multi-level framework for targeting HIV prevention efforts that address not only behavioral risk factors, but structural, political, and institutional factors associated with neighborhood disadvantage, levels of psychosocial stress, and prevention or treatment of HSV-2 and EBV.