Glioblastoma multiforme (GBM) is the most common malignant brain tumor that affects approximately 17,000 patients annually. Clear survival advantages have been demonstrated with postoperative radiation therapy (RT) to doses of 5,000-6,000 cGy but dose-escalation attempts beyond 6,000 cGy have resulted in increased toxicity but no additional survival benefit. To improve local control and limit toxicity to normal brain tissue with these infiltrating tumors, novel imaging techniques are actively being explored to better define tumor extent and associated RT treatment fields. Hyperfractionated RT has been associated with a survival detriment. Current standard-of-care treatment involves concurrent use of temozolomide and RT to 6,000 cGy over 30 days followed by adjuvant temozolomide treatment for 6 months. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but tend to be associated with notable toxicity. More recently, re-irradiation strategies employ concurrent use of bevacizumab to limit treatment-related injury while still permitting delivery of meaningful doses. These clinical trials are ongoing and merits of these strategies are not yet clear but appear promising.