This article outlines a conceptual framework for considering the genetic implications of childhood cancer and taking into account genetic predisposition as well as the genotoxic effects of cancer treatment. The primary consequences by which genetic effects are measured are somatic genetic damage, second tumors in the proband, germline genetic damage, and reproductive outcomes. Studies of retinoblastoma and rhabdomyosarcoma are offered as models for examining the etiology of genetic effects and defining the risks for a second malignant neoplasm. The conclusion from these studies is that there is a small subgroup of patients for whom the genetic implications of long-term survival are significant. Characteristics of this subgroup and the risks involved in treatment are defined. More optimistically, the data indicate that for the majority of patients, the risks involved in mutagenic and carcinogenic agents used in the treatment of childhood cancer are small. The authors conclude that treatment-related effects vary according to the genetic background of the proband.