The growth and metastasis of solid tumors critically depends on their ability to develop their own blood supply, a process known as tumor angiogenesis. Over the past decade much work has been performed to understand this process, and modifying this process provides a key point of therapeutic intervention in the fight against cancer. This Review explores the development of anti-VEGF-based antiangiogenic therapies, of which there are currently three licensed for clinical use worldwide. Although originally anticipated to inhibit the growth of tumor vessels, the induction of vascular normalization caused by these approved agents has provided a novel means of effective delivery of known chemotherapeutic agents. The development of small molecules that target VEGF receptors has resulted in the generation of inhibitors with not only vascular activity but antitumor activity in certain cancers. This Review will address the current status of vascular-disrupting strategies, such as therapies designed to induce tumor collapse by selectively destroying existing tumor vessels. These therapies can be broadly divided into small-molecular-weight vascular-disrupting agents and ligand-directed approaches. We discuss the current status of development, drug mechanisms of actions, combination with conventional chemotherapy and radiotherapy, and potential future targets for therapeutic intervention.