Vascular endothelial growth factor (VEGF) inhibitors have significantly improved outcomes in patients with advanced renal cell carcinoma (RCC). Multiple VEGF inhibiting orally administered tyrosine kinase inhibitors (TKIs) have been approved including sunitinib, sorafenib, pazopanib and most recently, axitinib. One VEGF inhibiting monoclonal antibody, bevacizumab, is approved in combination with interferon. However, these agents, besides the known progression-free survival benefits, are associated with a small but real risk of potentially life threatening and contrasting toxicities of thrombosis (both venous and arterial) and bleeding. Appropriate patient selection for VEGF inhibitors and prevention as well as prompt intervention to manage thrombosis and bleeding are necessary to forestall serious morbidities and mortality.