A significant body of evidence links the continued spread of infection with human immunodeficiency virus (HIV) with substance abuse. Some studies have shown changes in behavior which leave individuals at risk for acquiring and spreading HIV infection. Moreover, alcohol and illicit drugs are known to have a direct and toxic effect on the immune system, increase susceptibility to opportunistic infections, inadequate response to antiretroviral therapies, and exacerbate or uncover cognitive inefficiency. This review focuses on the emerging data of the immunomodulatory and toxic effects of alcohol and illicit drugs as well as nicotine. The use of these agents presents a special challenge because of the deleterious effects on HIVrelated disease and its progression to fully developed AIDS. There is an urgent need to recognize and incorporate this knowledge into collaborative care between medicine, infectious disease, addiction medicine and mental health professionals to inform treatment and management decisions.