Although we now know that childhood cancer survivors are likely to experience more cancers as adults than are individuals of similar age in the general population as a result of host-related factors (eg, deletion of the RB1 gene, which causes heritable retinoblastoma) and that certain aspects of anticancer treatment increase the risk of SMNs, our knowledge is constrained by the limited follow-up period (25 to 30 years) of the existing survivor cohorts. Not until there are large enough numbers of survivors in their fourth and fifth decades of life will we learn how normal aging processes and the “natural” increase of cancer in the general population influence the development of SMNs in survivors of childhood cancer.