Germline mutations in cancer causing genes result in high risk of developing cancer throughout life. These cancer predisposition syndromes (CPS) are especially prevalent in childhood brain tumors and impact both the patient's and other family members' survival. Knowledge of specific CPS may alter the management of the cancer, offer novel targeted therapies which may improve survival for these patients, and enables early detection of other malignancies. This review focuses on the role of CPS in pediatric high grade gliomas (PHGG), the deadliest group of childhood brain tumors. Genetic aspects and clinical features are depicted, allowing clinicians to identify and diagnose these syndromes. Challenges in the management of PHGG in the context of each CPS and the promise of innovative options of treatment and surveillance guidelines are discussed with the hope of improving outcome for individuals with these devastating syndromes.