Glioblastomas (GBM) are the most common and malignant primary tumors of the brain and are commonly treated with radiation therapy. Despite modest advances in chemotherapy and radiation, survival has changed very little over the last 50 years. Radiation therapy is one of the pillars of adjuvant therapy for GBM but despite treatment, recurrence inevitably occurs. Here we develop a mathematical model for the tumor response to radiation that takes into account the plasticity of the hierarchical structure of the tumor population. Based on this mathematical model we develop an optimized radiation delivery schedule. This strategy was validated to be superior in mice and nearly doubled the efficacy of each Gray of radiation administered. This is based on joint work with Ken Pitter, Eric Holland, and Franziska Michor.