Genetic inactivation of VHL causes the constitutive stabilisation of HIF-1α and HIF-2α, which induce gene expression programmes that play a central role in the pathogenesis of ccRCC by altering cellular metabolism, inducing angiogenesis, promoting epithelial-to-mesenchymal transition, invasion, and metastatic spread. The gene discussed is VHL; the disease is nonpapillary renal cell carcinoma.