This review is intended to provide a fundamental perspective on the dynamic interplay between HIV-1 and the immune system, an essential aspect in defining the pathogenesis and treatment of AIDS. HIV-1 infection, the cause of AIDS, is a worldwide pandemic with enormous adverse heath and economic implications, particularly in the developing world. This bloodborne and sexually transmitted disease, which evolved from simian immunodeficiency virus, infects and replicates in helper T cells and macrophages and utilizes CD4 and a chemokine coreceptor for entry. Immune deficiency occurs as a result of virally induced attrition of CD4 T cells, resulting in the development of opportunistic infections and malignancy. Prophylaxis against opportunistic infections is required according to the extent of immune deficiency. HIV-specific immunity can control viral replication and delay disease progression but does not clear infection. Antiretroviral treatment consists of inhibitors that target for viral entry, reverse transcriptase, and viral protease. Therapy can control viral replication, restore immunity, and delay disease progression, but it cannot eliminate infection. Thus chronic infection persists even in treated patients. Antiretroviral drugs have been highly effective in preventing mother-to-child transmission and for postexposure prophylaxis. Several novel vaccines in development hold promise for either effective infection prevention or attenuation of disease progression. (J Allergy Clin Immunol 2003;111:S582-92.)