Marsupial and eutherian mammals inactivate one X chromosome in female somatic cells in what is thought to be a means of compensating for the unbalanced X chromosome dosage between XX females and XY males. The hypothesis of X chromosome inactivation (XCI) was first published by Mary Lyon just over 50 years ago, with the discovery of XCI in marsupials occurring a decade later. However, we are still piecing together the evolutionary origins of this fascinating epigenetic mechanism. From the very first studies on marsupial X inactivation, it was apparent that, although therewere some similarities between marsupial and eutherianXCI, there were also some striking differences. For instance, the paternally derived X was found to be preferentially silenced in marsupials, although the silencing was often incomplete, which was in contrast to the random and more tightly controlled inactivation of the X chromosome in eutherians. Many of these earlier studies used isozymes to study the activity of just a few genes in marsupials. The sequencing of several marsupial genomes and the advent of molecular cytogenetic techniques have facilitated more in-depth studies into marsupial X chromosome inactivation and allowed more detailed comparisons of the features of XCI to be made. Several important findings have come from such comparisons, among which is the absence of the XIST gene in marsupials, a non-coding RNA gene with a critical role in eutherian XCI, and the discovery of the marsupial RSX gene, which appears to perform a similar role to XIST. Here I review the history of marsupial XCI studies, the latest advances that have been made and the impact they have had towards unravelling the evolution of XCI in mammals.