Over the last few years, renal cell carcinoma (RCC) has become a model disease for targeted therapeutics based on the growing understanding of the underlying molecular pathways in this disease. Clear cell RCC is characterized by the inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, which results in the dysregulation of hypoxia response genes, including an overproduction of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis, growth, and metastasis. In advanced RCC, substantial clinical activity has been reported with VEGF blockade employing a variety of approaches including antibodies and small-molecule VEGF receptor inhibitors. Many trials are still in progress with the goal of defining the optimal utility of these agents as monotherapy or in combination. This review will describe the current clinical data with VEGF-targeted approaches in RCC and plans for future development.