Approximately 10% to 15% of childhood cancers are hereditary or familial in nature. For several genetic disorders, the development of cancer is a secondary manifestation of the clinical phenotype, whereas cancer predisposition syndromes are generally recognized by the manifestation of characteristic malignancies. The study of pediatric cancer and rare hereditary cancer syndromes and associations has led to the identification of numerous cancer genes that are known to play critical roles in both normal and abnormal cellular growth, differentiation, and proliferation. The potential to identify such genetic markers of cancer predisposition poses difficult social, legal, and ethical questions in their application to clinical practice.