Although highly active antiretroviral therapy (HAART) has revolutionized the treatment of human immunodeficiency virus (HIV)-positive patients, malignancies in the setting of HIV infection remain an appreciable problem. We evaluated the changing epidemiology of HIV-related malignancies, optimal neoplastics and their effect on viral dynamics, and evidence regarding drug interactions between chemotherapy and antiretrovirals. A MEDLINE search (January 1966-June 2006) was performed to identify clinical trials, review articles, and meta-analyses; abstracts from HIV conferences were also searched. Survival of patients with HIV-related malignancies has substantially improved since the advent of HAART. Chemotherapy for malignancies in the HIV-positive population generally resembles that for the HIV-negative population, with trials revealing an elevated frequency of toxicities in HIV-positive patients. Studies of antineoplastics have shown no long-term adverse effects on viral dynamics in terms of immunologic or virologic HIV markers. Limited pharmacokinetic data with antineoplastics and antiretrovirals suggest possible changes in some pharmacokinetic parameters, but these results should be interpreted cautiously because of the small numbers of patients enrolled in the trials. Researchers also report an increased frequency of chemotherapy-related toxicities when HAART was coadministered with antineoplastics. This increase was likely due to impairment of cytochrome P450 metabolism of antineoplastics by protease inhibitors. Because of the survival benefits of HAART, the integration of antiretrovirals with chemotherapy is now preferred for patients with HIV-related malignancies. However, because the metabolic pathways of many of these agents are similar, the effectiveness of antineoplastic therapy and its related toxicities should be vigilantly monitored in this patient population.