The Staphylococcus aureus clonal complex CC121 is a common cause of human skin and soft-tissue infections, as well as the source of a recent epidemic in rabbits. Viana et al. track the evolution of the multi-host tropism of this lineage. Phylogenetic analysis based on whole-genome sequences of a global collection of CC121 clinical strains showed a high level of diversity for the strains isolated from human cases, whereas the strains isolated from rabbits fell into a single clade. The authors' analyses suggest that the most likely explanation for the emergence of the rabbit clade is a single human-to-rabbit host jump occurring more than 40 years ago. They demonstrate that a single naturally occurring mutation in the dltB gene is necessary and sufficient to convert a human-specific S. aureus strain into one that infects rabbits, and they find evidence for convergent evolution at this locus.