Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons, in which case the tumors are usually called diffuse brainstem gliomas. The diagnosis of supratentorial neoplasms is dependent on their histologic appearance. The maximum possible surgical resection is always attempted since the degree of surgical resection is the main prognostic factor for these patients. Older children (>3 years) with supratentorial neoplasms undergo a multimodality treatment comprised of surgical resection, radiation therapy, and chemotherapy. The addition of chemotherapy seems to improve the survival of a subset of these children, particularly those with glioblastoma multiforme. However, 2-year survival rates remain poor for children with supratentorial neoplasms, ranging from 10%-30%. The diagnosis of a diffuse brainstem glioma is based upon typical imaging, dispensing with the need for surgery in the majority of cases. Radiation therapy is the mainstay of treatment for children with diffuse brainstem gliomas. The role of chemotherapy for these children is not clear, and it is, in general, employed in the context of an investigational study. Less than 10% of children with diffuse brainstem gliomas survive 2 years. Because the outcome for patients with either type of tumor is poor when standard multimodality therapy is used, these children are ideal candidates for innovative treatment approaches.