Despite recent advances in operative techniques, chemotherapy, and radiotherapy, the prognosis in patients with glioblastoma multiforme (GBM) remains poor; the majority die within a year of diagnosis. Although often effective at reducing mass effect and tumor burden, surgical debulking and cytotoxic therapies have never demonstrated an unequivocally significant benefit in treating patients with GBM. This shortcoming has led to the development of molecules that target specific steps in the transduction pathways of high-grade glioma cells. In this article the authors review various cellular and extracellular signaling pathways that may prove promising in the treatment of patients with malignant glioma.