A new autochthonous genetically engineered mouse model of clear cell renal cell carcinoma (ccRCC) has been developed by combining deletion of the von Hippel–Lindau tumour suppressor gene (Vhl), Trp53 and Rb1 specifically in renal epithelial cells. Tumours arose from proximal tubule epithelial cells, the likely cell of origin of human ccRCC, and they recapitulated molecular markers and mRNA expression patterns of human ccRCC. Interestingly, exome sequencing demonstrated that tumours from both this mouse model and human ccRCC have recurrent mutations in genes associated with the primary cilium, an organelle that projects from the cell surface.