Glioblastoma (GBM) is the most common malignant brain tumor. Radiotherapy post surgical resection remained the mainstay of the management of GBM for decades until the addition of temozolomide was shown to prolong the median overall survival (OS) by 2.5 months to 14.6 months in 2005. Infiltrative growth to surrounding normal brain tissue and cooption of vascular niches, peripheral microvasuclar hyperplasia, and central hypoxic regions with pseudopalisading necrosis are characteristics of GBM and are causally linked to their exceptional radio- and chemo-resistant phenotype. An intratumoral hierarchy is postulated consisting of tumor stem cells in the apex with high DNA-repair proficiency resisting radiotherapy. It is conceivable that the stem cell property is more dynamic than originally anticipated. Niche effects such as exposure to hypoxia and intercellular communication in proximities to endothelial or bone marrow-derived cells (BMDC), for example, may activate such "stem cell" programs. GBM are exceptionally stroma-rich tumors and may consist of more than 70% stroma components, such as microglia and BMDC. It becomes increasingly apparent that treatment of GBM needs to integrate therapies targeting all above-mentioned distinct pathophysiological features. Accordingly, recent approaches in GBM therapy include inhibition of invasion (e.g., integrin, EGFR, CD95, and mTOR inhibition), antiangiogenesis and stroma modulators (TGFbeta, VEGF, angiopoetin, cMET inhibitors) and activation of immune response (vaccination and blockage of negative co-stimulatory signals). In addition, high LET-radiotherapy, for example with carbon ions, is postulated to ablate tumor stem cell and hypoxic cells more efficiently as compared with conventional low-LET photon irradiation. We discuss current key concepts, their limitations, and potentials to improve the outcome in this rapidly progressive and devastating disease.