With rapid scientific advances in HIV pathogenesis and antiretroviral therapy, the oncologist is faced with new challenges in the treatment of patients with HIV infection and malignancy. HIV infection, by causing immune dysregulation and cytokine production, may alter the natural history of certain neoplasms. Treatment of cancer with chemotherapy can also affect the course of HIV disease. The use of combination antiretroviral agents, particularly the protease inhibitors, can maximally suppress replication of HIV. Improved clinical outcome is associated with more profound decreases in plasma HIV RNA, although development of resistant strains may hinder sustained antiretroviral activity. Antiretroviral therapy should be continued during chemotherapy with the goal of achieving plasma HIV-RNA levels below 500 copies/mL. Modifications in the regimen should be done when intolerable toxicity occurs or if viral load is increased. Although information regarding the use of newer antiretroviral agents with chemotherapy is limited, the use of several reverse transcriptase inhibitors has been well tolerated in patients with AIDS-related malignancies such as Kaposi's sarcoma and lymphoma.