To address the roles of HIF-1α and HIF-2α in the development of ccRCC we take advantage of an accurate mouse model of ccRCC based on tamoxifen-inducible renal epithelial cell-specific deletion (Ksp-CreERT2) of Vhl, Trp53, and Rb116. The gene discussed is EPAS1; the disease is nonpapillary renal cell carcinoma.