Glioblastoma multiforme (GBM) – the highest-grade glioma and deadliest brain tumor – occurs in pediatric as well as adult patients. Despite aggressive treatment with surgery, irradiation and sometimes chemotherapy, tumors invariably recur as incurable lesions. Tumor cells with stem cell characteristics are thought to be responsible for therapeutic resistance in brain tumors. Despite the crucial role of radiation resistance in patient mortality, few viable therapeutic strategies have been identified to target these resistant cells. Using mouse models of glioma and primary human glioma cultures, we aim to characterize phenotypic intratumoral heterogeneity specifically with regards to radiation resistant stem-like tumor cells, the molecular signaling pathways underlying therapeutic resistance, and microenvironmental control over tumor cell phenotypes with the overall goal of developing novel therapeutic strategies targeting therapy-resistant cells in malignant brain tumors.