Comparisons of chromosome size, morphology and gene arrangements between mammals of different species permit us to deduce the genome characteristics of the common ancestor, and to chart the changes that have occurred during the divergence of the two lineages. The more distantly related are the species compared, the more remote the common ancestor whose characteristics can be deduced. This means that, providing there are sufficient similarities to warrant comparison, the more divergent the species compared, the more significant the contribution to our understanding of the organization of an ancestral mammalian genome and the process of mammalian genome evolution. One of the genetic surprises of the last decade was the discovery that, although gross karyotypes of distantly related orders of eutherian mammals (e.g. cat, cow, rabbit, man) have diverged extensively, gene mapping studies reveal the presence of large chromosome segments conserved across at least 60 million years (O'Brien et al. 1988). This finding makes it worthwhile to extend genetic comparisons to the two groups of mammals most distantly related to eutherian mammals--marsupials and monotremes. Here we will review comparisons of the sex chromosomes in these three major groups of extant mammals, and show how they have led us to a new view of the evolution of mammalian sex chromosome organization and function in sex determination and X chromosome inactivation.