Vascular endothelial growth factor (VEGF)–targeted therapy has become an important treatment option for the management of a number of human malignancies. Unfortunately, a significant number of patients do not respond to VEGF-targeted therapy when used as a single agent or in combination with chemotherapy. Furthermore, the duration of benefit from VEGF-targeted therapy can be relatively short (weeks to months). Ultimately, the vast majority of patients who initially respond to therapy will develop resistance. To date, the molecular and cellular mechanisms associated with resistance to VEGF-targeted agents are poorly understood. The mechanisms of action of anti-VEGF therapy are diverse, and it is entirely possible that resistance mechanisms are similarly diverse and depend on the tumor type. A better understanding of these mechanisms will help in the selection of those patients that are more likely to benefit from VEGF-targeted therapy and also provide for the rational development of therapies that circumvent or overcome resistance.