Developing ordered gene maps from multiple mammalian species coupled with chromosome-painting data provide a powerful resource for resolving the evolutionary history of chromosomes and whole genomes. In this work, we recapitulate the evolutionary history of human chromosome 1 and its homologs in placental mammals, putatively the largest physical unit in the ancestral placental genome. Precise definition of translocation exchange breakpoints in human, carnivore, cetartiodactyl, and rodent-ordered gene maps demonstrate that chromosome breakpoints, previously considered as equivalent, actually represent distinct chromosome positions and exchange events. Multidirectional chromosome painting, using probes from homologs to chromosome 1 in seven mammal species from six orders of placental mammals, confirm the gene-mapping results and indicate that the multiple human chromosome 1 homologs in these species are derived from independent fissions of a single ancestral chromosome. Chromosome painting using human chromosome 1 probes identifies a single human chromosome 1 homolog in phylogenetically distant taxa, the two-toed sloth, cetaceans, and higher primates. The diverse phylogenetic occurrence of a single Hsa1 synteny among the major clades of placental mammals suggests that human chromosome 1 represents an intact ancestral chromosome, which was variously fissioned in the majority of placental species. We find that the number of human chromosome 1 fissions in a specific lineage reflects its general rate of genomic evolution. Further, historic chromosome exchange appears to have been disproportionately clustered in two breakpoint hotspots on the long arm.