Management of renal cell carcinoma (RCC) has made considerable strides in the past decade, due in large part to identification of the von Hippel Lindau (VHL) tumor suppressor as a negative regulator of hypoxia inducible factor alpha (HIF-alpha) protein expression. Stabilization of HIF-alpha appears to be critical for renal tumorigenesis, and is observed even in VHL-independent RCC. Thus, an understanding of the pathways that regulate expression and activation of the different HIF-alpha isoforms is key to delineating the mechanism of renal transformation and for the development of novel therapeutics. A number of agents targeting HIF-alpha or its transcriptionally-regulated genes have shown promise in treatment of RCC. However, more effective treatment strategies are still needed. This report provides a directed review of recent discoveries defining the role of HIF in renal tumorigenesis and their relevance to the clinical advances in targeted therapy for advanced RCC.