Precision medicine has emerged with the advancement of genetic technologies and knowledge of molecular pathogenesis. A clinical translation of precision medicine in pediatric oncology lies in hereditary cancer predisposition syndromes, which plague approximately 10% of patients and families. Proper identification of these patients, appropriate genetic testing and counseling, and an understanding of short-term treatment implications and long-term screening protocols are all essential to comprehensive care for patients and families with cancer predisposition syndromes. Current knowledge of pediatric cancer predisposition syndromes, referral and identification, and treatment and long-term follow up will be discussed. Moreover, a case series and easy reference tools for clinical practice will be presented.