The genetic changes that enable pathogens to jump from one host species to another, which often results in epidemic disease, are poorly understood. To identify the molecular basis of host adaptation, Penadés and colleagues traced the evolutionary history of Staphylococcus aureus ST121, which switched its host preference from humans to rabbits more than 40 years ago. Using whole-genome sequencing of both present-day and historical human and rabbit isolates, the authors found that only a single nonsynonymous mutation in the core genome was required and sufficient for host switching. Interestingly, the mutated gene, dltB, had also acquired nonsynonymous mutations in seven other S. aureus strains that had switched host specificity from humans to rabbits, as well as in a soil-borne strain of Bacillus amyloliquefaciens that had adapted from a plant-root niche. This convergent evolution suggests that dltB has an important function in defining host tropism, but establishing the mechanism that links the gene to host specificity requires further study.