The percentage of childhood cancers that are caused by a clearly inherited predisposition varies significantly from only a few percent to more than 50% with individual tumor types. Recent advances in genetic testing and studies of cohorts of cancer patients have demonstrated the likelihood of identifying a cancer susceptibility mutation for numerous childhood cancers. Inherited predisposition to cancer is frequently the result of dominant constitutional mutations in tumor suppressor genes, which can be inherited from an affected parent or occur de novo during gametogenesis. In this article, we review the childhood malignancies that are associated with at least a 10% likelihood of being caused by a genetic susceptibility to cancer and therefore warrant consideration for a genetic evaluation; these malignancies include retinoblastoma, adrenocortical carcinoma, atypical teratoid and malignant rhabdoid tumors, optic pathway tumors, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, vestibular schwannomas, endolymphatic sac tumors, hemangioblastomas, medullary thyroid cancer, pheochromocytomas, and paragangliomas. Children with other malignancies may also warrant genetic evaluation if there is the co-occurrence of malignancy and two or more congenital anomalies, or malignancy and a significant family history of related cancers. We also review the importance of the correct genetic diagnosis in order to ensure appropriate treatment and ongoing cancer surveillance for the child with cancer and closely related family members (e.g., parents and siblings).