© 2016, Millennium Medical Publishing, Inc. All rights reserved. The arrival of targeted therapies—vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) inhibitors—and programmed death 1 (PD-1) inhibitors has transformed the management of renal cell carcinoma (RCC). Once considered fatal, with a median survival of approximately 1 year, these agents have nearly tripled overall survival and have raised hopes of a possible cure for advanced RCC. This review begins with a brief discussion of the seminal von Hippel-Lindau/ hypoxia-inducible factor axis in RCC. It then discusses the pivotal trials that have investigated VEGF inhibitors in metastatic RCC, as well as in adjuvant and neoadjuvant settings. Finally, it addresses some practical considerations and future directions in the use of VEGF inhibitors in RCC.