Unlike autosomal genes, the majority of X-linked genes are subject to dosage compensation. As a result, female tissues comprise cells exclusively expressing X-linked genes from one or other parent. The implication of having only one allele of active X-linked genes in cancer pathogenesis, i.e. somatic single-hit inactivation and dominant inheritance, has not been extensively explored. Recent studies have identified FOXP3 and WTX as two X-linked tumor suppressor genes that are somatically inactivated by single genetic hits. Because the predicted dominant inheritance of cancer risk has not been demonstrated in humans, we will discuss the possible conditions that might prevent such dominant inheritance. We also argue that the existence of a genetically intact allele in cancer cells in women, together with apparent abnormal X inactivation in cancer cells, might provide an opportunity to selectively reactivate tumor suppressor genes for cancer therapy. © 2010 Elsevier Ltd.