Since the advent of HAART, patients with HIV infection have seen a significant improvement in their morbidity, mortality, and life expectancy. The incidence of AIDS-defining illnesses, including AIDS-defining malignancies, has been on the decline. However, deaths due to non-AIDS-defining illnesses have been on the rise. These so-called non-AIDS-defining cancers (NADCs) include cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin's lymphoma. It is poorly understood why this higher rate of NADCs is occurring. The key challenge facing oncologists is how to administer chemotherapy effectively and safely to patients on antiretroviral therapy. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on the epidemiology and etiology of NADCs, as well as ongoing research into this evolving aspect of the HIV epidemic.