Our observation that KDM5C mutation is accompanied by loss of the Y chromosome in most male ccRCC tumours is instead consistent with the idea that KDM5C and KDM5D may follow a modification of a classic Knudson two-hit tumour suppressor function that applies to sex chromosome gene homologues rather than alleles of the same gene. The gene discussed is KDM5D; the disease is nonpapillary renal cell carcinoma.