Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy (RT). Several randomized trials conducted over the past 30 years have failed to show a significant survival advantage for patients treated with BCNU or PCV chemotherapy. The randomized EORTC 26981/22981-NCIC trial has clearly demonstrated that the addition of the methylating agent temozolomide (TMZ) to RT followed by 6 monthly cycles of TMZ provides significant survival benefit with minimal additional toxicity in patients with GBM. A recent analysis of the trial revealed longer survival in patients with GBM which exhibited the methylation of the promoter region of the O (6)-methylguanine DNA methyltransferase (MGMT) gene. In patients with unfavourable prognostic factors, such as older age and poor performance status, abbreviated courses of RT in association with TMZ may be employed as an alternative to more aggressive treatments. Identification of many molecular genetic and signal transduction pathways involved in gliomatogenesis have yielded to the development of several targeted drugs, including epidermal growth factor receptor (EGFR) tyrosin kinase inhibitors, antiangiogenic agents, and integrin inhibitors, that are currently tested in combination with TMZ and RT. This review summarizes the results of chemoradiation for GBM and the development of new strategies under evaluation to increase the efficacy of treatments.