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Vascular endothelial growth factor (VEGF) is a key mediator in the pathogenesis of renal cell carcinoma (RCC). VEGF is up-regulated in clear cell RCC as a result of loss of the von Hippel-Lindau tumor suppressor gene and subsequent activation of the hypoxia response pathway. VEGF expression drives the migration and proliferation of endothelial cells to support the extensive angiogenesis in RCC. Strategies have been developed to bind and neutralize VEGF and have been investigated in RCC with promising results. Bevacizumab, a VEGF ligand-binding antibody, has shown prolonged time-to-progression versus placebo in treatment-refractory RCC patients and is being investigated currently in multiple RCC settings. VEGF-Trap is also a VEGF binding molecule with ongoing investigation in RCC.