Currently, adult glioblastoma (GBM) patients have poor outcomes with conventional cytotoxic treatments. Because GBMs are highly angiogenic tumors, inhibitors that target tumor vasculature are considered promising therapeutic agents in these patients. Encouraging efficacy and tolerability in preliminary clinical trials suggest that targeting angiogenesis may be an effective therapeutic strategy in GBM patients. However, the survival benefits observed to date in uncontrolled trials of antiangiogenic agents have been modest, and several obstacles have limited their effectiveness. This article reviews the rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in GBM patients. Although challenges remain with this approach, ongoing studies may improve upon the promising initial benefits already observed in GBM patients.