A new autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) could be used to investigate ccRCC biology and test new therapies. Combined deletion of Vhl, Trp53 and Rb1 in renal epithelial cells induced the development of ccRCC tumours that arose from the proximal tubule and had similar cellular and molecular features to human ccRCC, including recurrent mutations in genes associated with the primary cilium. Different mouse tumours responded differently to ccRCC therapies and to HIF-α inhibition, suggesting that the model could be a useful tool for the identification of molecular determinants of tumour sensitivity and resistance.