Effective treatment of glioblastoma multiforme (GBM) is complicated by multiple factors, including the diffusely infiltrative nature of the disease, which limits complete surgical resection; the difficulty in overcoming the blood-brain barrier with systemic therapies; and the challenge of identifying novel means of treating the residual hypoxic tumor cells that are relatively resistant to radiotherapy (RT) and chemotherapy. Clear survival advantages have been demonstrated with postresection RT to doses of 5,000-6,000 cGy, but further attempts at dose escalation over 6,000 cGy have resulted in increased toxicity without a survival benefit. In an effort to improve local control of tumor and limit toxicity to normal brain tissue, novel imaging techniques (eg, chemical shift imaging) are being explored in order to better define RT fields. Brachytherapy and stereotactic radio-surgery are effective therapies for relapsed GBM but have undefined roles outside of clinical trials in treating newly diagnosed GBM. Stereotactic RT may have a survival advantage in subgroups that have undergone a gross total resection and have favorable (recursive partitioning analysis class IV) disease. In contrast, experience with hyperfractionated RT in GBM has shown that survival outcomes may actually be unfavorable in certain patient subgroups. Novel means of delivering RT, including radioimmunotherapy, have demonstrated efficacy with acceptable toxicity. Systemic agents are being explored as potential radiosensitizers, with the recent emergence of temozolomide as a model radiosensitizing agent having a positive impact on survival. Ongoing investigations are evaluating temozolomide in combination with other systemic agents, and additional agents (eg, motexafin gadolinium, mammalian target of rapamycin inhibitors, farnesyltransferase inhibitors) have shown promising activity in combination with RT.