Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.