Numerous antiangiogenic agents with diverse mechanisms of action are currently under investigation for the treatment of patients with glioblastoma (GBM), a diagnosis that continues to carry a poor prognosis despite maximal conventional therapy. Early clinical trials suggest that antiangiogenic drugs, which target the blood vessels of these highly angiogenic tumors, may have clinical benefit in GBM patients. Antiangiogenic agents have potent antiedema and steroid-sparing effects in patients, and emerging data suggest that these drugs may modestly improve progression-free survival. Although these early results are encouraging, several issues arise regarding the use and efficacy of these agents. Interpretation of the radiographic changes that occur after treatment with antiangiogenic agents presents a major challenge. Still lacking are reliable radiographic and biologic markers that can predict which patients will benefit from treatment and that accurately indicate response and progression during therapy. In addition, most patients treated with antiangiogenic drugs eventually progress, and the mechanisms by which tumors escape from therapy are only beginning to be understood. Larger prospective trials that incorporate correlative biomarker studies will be required to address these challenges. Here, we summarize the clinical experience with antiangiogenic therapy in patients with malignant gliomas (MG), review the major issues concerning the use and development of these agents, and discuss strategies that may build upon the initial gains observed with antiangiogenic agents.