Despite the high radiographic response rate in recurrent glioblastoma to antiangiogenic therapy, the impact of these agents on improving overall survival have been disappointing. A lack of survival benefit has resulted in an increased effort to better understand the mechanisms underlying resistance to antiangiogenic therapy. Adaptive (evasive) resistance and intrinsic (pre-existing) nonresponsiveness have emerged as modes of resistance to antiangiogenic therapy with multiple mechanisms believed to contribute to each type. This increasing knowledge regarding these mechanisms of resistance has led to an increased focus on the tumor microenvironment in aiding in the determination of the optimal biologic dose of antiangiogenic therapy. Although there is a lack of durable responses to current antiangiogenic treatments, there is an important role for angiogenesis inhibitors in the treatment of high-grade gliomas. Current efforts are underway regarding optimizing antiangiogenic therapy as an adjunctive treatment to radiation and chemotherapy.