Despite the implementation of increasingly aggressive surgery, chemotherapy, and fractionated radiotherapy for the treatment of glioblastoma multiforme (GBM), most therapeutic regimens have resulted in only modest improvements in patient survival. Gamma knife surgery (GKS) has become an indispensable tool in the primary and adjuvant management of many intracranial pathologies, including meningiomas, pituitary tumors, and arteriovenous malformations. Although it would seem that radiosurgical techniques, which produce steep radiation dose fall-off around the target, would not be well suited to treat these infiltrative lesions, a limited number of institutional series suggest that GKS might provide a survival benefit when used as part of the comprehensive management of GBM. This may largely be attributed to the observation that tumors typically recur within a 2-cm margin of the tumor resection cavity. Despite these encouraging results, enthusiasm for radiosurgery as a primary treatment for GBM is significantly tempered by the failure of the only randomized trial that has been conducted to yield any benefit for patients with GBM who were treated with radiosurgery. In this paper, the authors review the pathophysiological mechanisms of GKS and its applications for GBM management.