Purpose CNS malignancies are currently the most common cause of disease related deaths in children. Although brainstem gliomas are invariably fatal cancers in children, clinical studies against this disease are limited. This review is to lead to a succinct collection of knowledge of known biological mechanisms of this disease and discuss available therapeutics. Methods A hallmark of brainstem gliomas are mutations in the histone H3.3 with the majority of cases expressing the mutation K27M on histone 3.3. Recent studies using whole genome sequencing have revealed other mutations associated with disease. Current standard clinical practice may merely involve radiation and/or chemotherapy with little hope for long term survival. Here we discuss the potential of new therapies. Conclusion Despite the lack of treatment options using frequently practiced clinical techniques, immunotherapeutic strategies have recently been developed to target brainstem gliomas. To target brainstem gliomas, investigators are evaluating the use of broad non-targeted therapy with immune checkpoint inhibitors. Alternatively, others have begun to explore adoptive T cell strategies against these fatal malignancies.