Diffuse brain stem glioma is the most devastating of pediatric malignancies. Virtually all children with this disease die within 1–2 years of diagnosis. After three decades of exhaustive research, the key to controlling this malignancy still eludes us. Attempts to improve survival using radiation, chemotherapy and biologic agents have yet to culminate in meaningful advances. Recent advances in molecular biology have led to the development of more targeted therapies, which are now being introduced in clinical trials for children with brain stem glioma. As our understanding of the biology of this disease improves, so too will our ability to target it more effectively. Real strides in improving the lives of children with brain stem glioma may finally be within our grasp.