Angiogenesis, a key process for the growth of human cancers, has recently been exploited for the development of a novel class of cancer therapeutics that was thought to have wide applications and not to induce resistance in the clinical setting. Indeed, anti-angiogenic therapy has become an important option for the management of several human malignancies. However, a significant number of patients either do not respond to anti-angiogenic agents or fairly rapidly develop resistance. In addition, the benefit of anti-angiogenic therapy is relatively short-lived and the majority of patients eventually relapses and progresses. Several mechanisms of resistance to anti-angiogenic therapy have been recently proposed. The current review focuses on the role of intra-tumor hypoxia as a mechanism of resistance to anti-angiogenic agents and speculates on therapeutic approaches that might circumvent resistance and thereby improve clinical outcome.