Pediatric high-grade gliomas, including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma, are difficult to treat and are associated with an extremely poor prognosis. For several decades, radical and safe surgical resection and radiotherapy have formed the cornerstone of therapy for pediatric high-grade gliomas. However, for the majority of affected children, these modalities only provide short-term clinical benefits and disease control, with the vast majority of these patients experiencing disease progression within 2 years. The infiltrative nature and the intrinsic radio-resistance of these tumors are believed to be the major contributors to the dismal prognosis displayed by these tumors. There are no effective chemotherapeutic regimens for the treatment of these tumors, but many new treatment options are in active investigation. The current belief is that multimodal therapy holds the greatest promise for pediatric high-grade gliomas.