With the advent of effective combination antiretroviral therapy, HIV infection has been transformed from a fatal disease to a chronic condition. There is renewed clinical interest in long-term morbidities, including malignancies that occur disproportionately within this population. Non-AIDS-defining cancers (NADCs) are a significant source of morbidity and mortality in the aging HIV-infected population. There are data to suggest that incidence rates are elevated among HIV-infected individuals for many cancer sites, particularly those with a confirmed or suspected infectious etiology. The complex interplay between behavioral risk factors, coexistence of viral infections, immunodeficiency and antiretroviral therapy makes it difficult to analyze why certain cancers develop more frequently in HIV-infected individuals. 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 whether NADCs are increased in the HIV-Infected population, as well as ongoing research on epidemiology, prevention and pathogenesis of this evolving aspect of the HIV epidemic.