Clear cell renal cell carcinoma (ccRCC) provides a tumor paradigm for the integration of genetics, molecular biology, therapeutic target validation and the introduction of high-impact treatment strategies. Most cases of sporadic as well as familial ccRCC acquire somatic inactivating mutations of the von Hippel–Lindau tumor-suppressor gene, VHL. pVHL, VHL gene product and a protein member of the E3 ubiquitin ligase family, acts in normal cells to direct the degradation and clearance of the hypoxia inducible factor (HIF)α transcription factor family, such that in its absence, as in ccRCC, the HIF proteins stabilize, accumulate to supraphysiologic levels and activate the transcription of genes such as VEGF and PDGF, which contributes substantially to the physiology of the tumor, and has been assessed indirectly as a prognostic factor. Molecularly targeted therapy blocking components of this pathway has been successfully introduced to the clinic with a substantive impact on clinical parameters of RCC. This review will examine the regulation of these molecular pathways in RCC and discuss the impact on the clinical management of patients with RCC.