Solid tumors are consistently less well-oxygenated than the normal tissues from which they arise. Associations between tumor hypoxia and aggressively malignant phenotypes are observed across a range of cancers, focusing attention on molecular dissection of these pathways and how they contribute to tumorigenesis. Clear cell renal cell carcinoma (ccRCC) is characterized by a loss of the tumor suppressor gene VHL, and hence this tumor type is characterized by constitutive activation of the hypoxic response. As such, it represents a model system for tumor hypoxia in general. Our research is aimed at identifying and characterizing the different cell types from which kidney cancer is thought to develop, and to characterize how they respond to hypoxia and loss of VHL. We have also defined as a novel ccRCC specific biomarker, SLC6A3, and explore the diagnostic and therapeutic potential of this protein. We have previously shown that hyperactivated Notch signaling may complement loss of VHL in the formation of ccRCC. Based on these findings we are establishing a model system for ccRCC based on conditional deletion of VHL in conjunction with constitutive activation of the Notch signaling pathway.