Retinoblastoma and Wilms’ tumor represent two childhood tumors with both sporadic and familial forms. Delineation of the molecular etiology of these cancers identified the retinoblastoma gene Rb as the first example of a tumor suppressor gene and provided the first example of imprinting and cancer predisposition in Wilms’ tumor. In this chapter, we review the clinical features and genetics of these two disorders and the implications for management, early detection and potential prevention of these disorders.