In the past 3 decades, the number of cancer survivors in the United States has tripled, reaching approximately 10.7 million in 2004. Although cancer survivors now comprise about 3.5% of the population, subsequent malignancies among this high-risk group account for about 16% (or 1 in 6) of all cancer incidence. Multiple primary cancers can reflect the influence of antecedent cancer therapy, shared etiologic factors, environmental exposures, genetic susceptibility, lifestyle choices, other factors, and the combinations of effects, including gene-environment and gene-gene interactions. Survivors of individual types of primary cancers are at increased risk for distinctive types of subsequent neoplasms. Careful documentation of the magnitude and temporal patterns of these site-specific excess risks, as well as delineation of the contribution of treatment exposures and other factors, will facilitate the development of optimal follow-up plans. Management approaches should include patient education, screening, and prevention strategies. An improved understanding of those malignancies that are largely treatment-related will facilitate the formulation of customized therapeutic approaches for newly diagnosed cancer patients aimed at minimizing the risk of subsequent neoplasms and other late effects, without compromising cure rates.