Males have a higher risk than females of developing many cancers but the reasons for this disparity are unclear. Dunford et al. analysed exome sequences of 4,126 tumours across 21 cancer types and identified some tumour suppressor genes on the X chromosome that escape X-inactivation in females. Loss-of-function mutations in six of these genes were more common in male than in female tumours; as females would require two deleterious mutations to inactivate these genes, this might explain some of the reduced cancer incidence in females.