Almost from the time it was first described (Lyon,1961), mammalian X-chromosome inactivation has been looked upon as a means of dosage compensation, to balance the activity of X-linked genes between males (AAXY) and females (AAXX). The question of how the two sexes managed to avoid the consequences of X-chromosome monosomy was left unaddressed until Ohno (1967) proposed a two-step evolutionary process involving, first, enhancement of the rate of transcription of the single X chromosome in the male such that the product levels of X-linked genes and those of the two sets of autosomal genes are similar. But in the XX female such enhancement would be expected to push the levels of X-linked gene products to potentially harmful tetrasomic levels. Ohno therefore reasoned that the function of X inactivation is to bring down X-linked gene activity to disomic levels. For over 40 years Ohno's hypothesis has been a widely used framework for thinking about the evolution of heteromorphic sex chromosomes in mammals, X inactivation and dosage compensation.