Angiogenesis is a key event of tumor progression and metastasis and hence a target for cancer chemotherapy. Therapeutic strategies focused on angiogenesis include the discovery of new, targeted anti-angiogenic agents and the re-evaluation of conventional anti-cancer drugs. Here, we review the most recent studies investigating the molecular and cellular mechanisms responsible for the anti-angiogenic activity of microtubule-targeting agents (MTAs). These agents include some of the most widely used and effective antitumor drugs that are also among the most anti-angiogenic. In addition, we summarize the latest results of pre-clinical and clinical studies involving MTAs administered at low metronomic doses and in anti-angiogenic combination strategies. Finally, we discuss the future development of these agents, their clinical potential and their limitations.