Marsupials are "alternative mammals" that differ from eutherians most spectacularly in their mode of reproduction and sexual differentiation. They represent a 160-million-year-old isolate from the more numerous eutherians, making them particularly valuable for comparative genome studies that enlarge and enhance our understanding of the function and evolution of the mammalian genome. The genomes of three sequenced marsupial species are similar in size to those of mice and humans but show informative differences in base composition and repetitive elements. Small differences in gene sets and gene families between marsupials and eutherians may relate to physiological and environmental differences. Marsupial karyotypes are highly conserved in chromosome numbers, sizes, and G-banding patterns, and an ancestor with a 2n = 14 karyotype can be deduced. Marsupial sex chromosomes, partly homologous to those of eutherians, represent the ancestral therian XY pair. Epigenetic regulation of X inactivation in marsupials differs markedly from that of eutherians and has apparently retained an ancient silencing mechanism. Genomic imprinting of a smaller set of genes occurs in the marsupial placenta and, uniquely, in the mammary gland.