Angiogenesis is the outgrowth of new blood vessels from the preexistent vasculature. In 1971, Folkman hypothesized that solid tumors are dependent on angiogenesis for sustained growth and that anti-angiogenic treatment is a potential antineoplastic therapy. Because glioblastoma multiforma (GBM) frequently shows florid microvascular proliferation (MVP), this tumor has been considered since then as a suitable candidate for such treatment that attempts to eradicate or control a neoplasm by interfering with its blood supply. Indeed, in animal models the growth of glioma xenografts can be inhibited by targeting the angiogenic process. However, unlike many glioma xenografts, human infiltrating gliomas such as GBMs have a diffuse infiltrative growth pattern, and preexistent vessels may suffice to provide many tumor cells with much of their blood supply, particularly in the critical peripheral infiltrative margins. Thus, while attractive in concept, anti-angiogenic therapy of GBM must address the anatomic vascular realities of this neoplasm. Even if anti-angiogenic therapy ultimately has a role in infiltrative neoplasms, there are a host of other intracranial neoplasms whose discrete architecture might make them attractive candidates for anti-angiogenic therapy. This review summarizes the angiogenic process in GBM and suggests other types of tumors for which the efficacy of anti-angiogenic therapy might be studied.