In the highly active antiretroviral therapy (HAART) era, the incidence of non-AIDS-defining cancers (NADC) has increased and contributes to a growing proportion of mortality in the aging HIV-infected population. The underlying pathogenic mechanisms of increased cancer risk are incompletely understood. Potential contributors include oncogenic effects of the HIV virus, immunosuppression, chronic inflammation and immune activation, exposure to HAART, higher rates of oncogenic viral coinfections and traditional cancer risk factors. HIV-infected patients often present with NADC at younger ages with more aggressive or advanced stage disease. However, when standard cancer therapy is given, treatment outcomes appear similar to the non-HIV population. These facts highlight the importance of clinicians' maintaining a high index of suspicion, performing age-appropriate screening, and optimizing cancer therapy. Development of novel strategies for screening, prevention, and treatment of NADC will be required to reverse these epidemiologic trends and improve the survival of HIV-infected patients.