Inactivation of the VHL tumor suppressor protein (pVHL) is a common event in clear cell renal carcinoma, which is the most common form of kidney cancer. pVHL performs many functions, including serving as the substrate recognition module of an ubiquitin ligase complex that targets the alpha subunits of the heterodimeric HIF transcription factor for proteasomal degradation. Deregulation of HIF2α appears to be a driving force in pVHL-defective clear cell renal carcinomas. In contrast, genetic and functional studies suggest that HIF1α serves as a tumor suppressor and is a likely target of the 14q deletions that are characteristic of this tumor type. Drugs that inhibit HIF2α, or its downstream targets such as VEGF, are in various stages of clinical testing. Indeed, clear cell renal carcinomas are exquisitely sensitive to VEGF deprivation and four VEGF inhibitors have now been approved for the treatment of this disease.