In most discussions of the evolution of sex chromosomes, it is presumed that the morphological differences between the X and Y were initiated by genetic changes. An alternative possibility is that, in the early stages, a key role was played by epigenetic modifications of chromatin structure that did not depend directly on genetic changes. Such modifications could have resulted from spontaneous epimutations at a sex‐determining locus or, in mammals, from selection in females for the epigenetic silencing of imprinted regions of (...) the paternally derived sex chromosome. Other features of mammalian sex chromosomes that are easier to explain if the epigenetic dimension of chromosome evolution is considered include the relatively large number of X‐linked genes associated with human brain development, and the overrepresentation of spermatogenesis genes on the X. Both may be evolutionary consequences of dosage compensation through X‐inactivation. BioEssays 26:1327–1332, 2004. © 2004 Wiley Periodicals, Inc. (shrink)