Primary glial brain tumors account for the majority of primary brain tumors in children. They are classified as low-grade gliomas (LGG) or high-grade gliomas (HGG), based on specific pathologic characteristics of the tumor, resulting in disparate clinical prognoses. Surgery is a mainstay of treatment for HGG, although it is not curative, and adjuvant therapy is required. Temozolomide, an oral imidazotetrazine prodrug, while considered standard of care for adult HGG, has not shown the same degree of benefit in the treatment of pediatric HGG. There are significant biologic differences that exist between adult and pediatric HGG, and targets specifically aimed at the biology in the pediatric population are required. Novel and specific therapies currently being investigated for pediatric HGG include small molecule inhibitors of epidermal growth factor receptor, platelet-derived growth factor receptor, histone deacetylase, the RAS/AKT pathway, telomerase, integrin, insulin-like growth factor receptor, and γ-secretase. Surgery is also the mainstay for LGG. There are defined front-line, multiagent chemotherapy regimens, but there are few proven second-line chemotherapy options for refractory patients. Approaches such as the inhibition of the mammalian target of rapamycin pathway, inhibition of MEK1 and 2, as well as BRAF, are discussed. Further research is required to understand the biology of pediatric gliomas as well as the use of molecularly targeted agents, especially in patients with surgically unresectable tumors.