Mammalian X and Y chromosomes evolved from an autosomal pair; the X retained and the Y gradually lost most ancestral genes,. In females, one X chromosome is silenced by X inactivation, a process that is often assumed to have evolved on a broadly regional or chromosomal basis. Here we propose that genes or clusters common to both the X and Y chromosomes (X–Y genes) evolved independently along a multistep path, eventually acquiring dosage compensation on the X chromosome. Three genes studied here, and other extant genes, appear to be intermediates. ZFX, RPS4 and SMC were monitored for X inactivation in diverse species by assaying CpG-island methylation, which mirrors X inactivation in many eutherians. ZF evidently escaped X inactivation in proto-eutherians, which also possessed a very similar Y-linked gene; both characteristics were retained in most extant orders, but not in myomorph rodents. For RPS4, escape from X inactivation seems unique to primates. SMC escapes inactivation in primates and myomorphs but not in several other lineages. Thus, X inactivation can evolve independently for each of these genes. We propose that it is an adaptation to the decay of a homologous, Y-linked gene.