To define the role, if any, of HIF activation in FH-associated neoplasia, we combined inactivation of Fh1 with Hif-1α, Hif-2α, or both Hif-α isoforms, measured the frequency of renal cyst formation in a mouse model recapitulating the cystic phenotype of the human disease, and compared the outcome with that of genetic inactivation of the Hif prolyl hydroxylases (Phds). The gene discussed is EPAS1; the disease is cystic kidney disease.