While numerous mouse models have shown that neither genetic deletion of Vhl, nor stabilization of HIF-1α and HIF-2α alone or together in renal epithelial cells are sufficient to cause tumor formation in mouse kidneys (reviewed in [7]), we have recently shown that both HIF-1α and HIF-2α are necessary for the initiation of renal cysts and tumors in Vhl/Trp53 mutant mice [8]. The gene discussed is EPAS1; the disease is cystic kidney disease.