Marsupials typically possess very large, distinctive chromosomes that make them excellent subjects for cytogenetic analysis, and the high level of conservation makes it relatively easy to track chromosome evolution. There are two speciose marsupial families with contrasting rates of karyotypic evolution that could provide insight into the mechanisms driving genome reshuffling and speciation. The family Dasyuridae displays exceptional karyotype conservation with all karyotyped species possessing a 2n = 14 karyotype similar to that predicted for the ancestral marsupial. In contrast, the family Macropodidae has experienced a higher rate of genomic rearrangement and one genus of macropods, the rock-wallabies (Petrogale), has experienced extensive reshuffling. For at least some recently diverged Petrogale species, there is still gene flow despite hybrid fertility issues, making this species group an exceptional model for studying speciation. This review highlights the unique chromosome features of marsupial chromosomes, particularly for these two contrasting families, and the value that a combined cytogenetics, genomics, and epigenomics approach will have for testing models of genome evolution and speciation.