Vascular endothelial growth factor (VEGF) has been identified as the most potent cytokine involved in tumor angiogenesis and metastasis formation. Clinical results of anti-angiogenic therapies targeting VEGF and its receptors are very modest, resulting in a moderate improvement of overall survival. The clinical outcome is associated with the development of resistance and the increased risk of invasion and metastasis. In this article, I have analyzed the principal mechanisms of resistance to VEGF pathway inhibitors, including normalization of tumor blood vessels, hypoxia, recruitment of inflammatory cells and immature myeloid cells, alternative mechanisms of tumor vessel formation, genomic instability of tumor endothelial cells. In this context, the concept and strategies of anti-angiogenic therapies should be extensively re-considered and re-evaluated. In particular, rational combinations of anti-angiogenic agents based on pharmacokinetic and pharmacodynamics data are needed to overcome resistance and it is extremely important to determine the optimal duration and scheduling of anti-VEGF agents.