Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene–environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)–sponsored workshop entitled “Cancer Survivorship—Genetic Susceptibility and Second Primary Cancers.” These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.