HIV/AIDS continues to be a significant public health problem. Millions of people worldwide are infected with this virus daily, and thousands die yearly of AIDS-related illnesses. Despite rapid advances in our knowledge about HIV and its mode of transmission, we have been unable to find a cure or prevent new infections. Psychiatric comorbidity is associated with HIV/AIDS: as a risk factor for HIV infection, a comorbidity of HIV infection, sequelae of HIV/AIDS, and a potential mediator for progression to AIDS. In this article, we focus on depression, which is prevalent in HIV/AIDS. We review the evidence associating depression with HIV, the challenges in recognizing depression in HIV-positive individuals, and the psychopharmacologic strategies known to be effective in the treatment of HIV-positive individuals with depression.