Adults with glioblastoma multiforme (GBM), the most common primary brain tumor, have an unacceptably poor outcome with conventional cytotoxic therapies. Malignant gliomas are remarkably angiogenic, and vascular endothelial growth factor (VEGF) is the dominant pro-angiogenic factor. Recent clinical trials targeting VEGF signaling have achieved unprecedented rates of durable radiographic and clinical response, while also confirming adequate safety among recurrent malignant glioma patients. An array of additional clinical trials evaluating anti-angiogenic strategies are underway for both recurrent and newly diagnosed malignant glioma patients. Promising results of these approaches suggest that the treatment of GBM may represent an emerging paradigm of anti-angiogenic therapy.