The emergence of new pathogens is a major threat to public and veterinary health. Staphylococcus aureus is a multi-host bacterial pathogen and one of the leading causes of antibiotic resistance-associated mortality worldwide. While S. aureus is notorious as a human pathogen, its evolutionary history is marked by numerous host-switching events between humans and livestock in both directions leading to the emergence of new pathogenic clones circulating in distinct host populations. In this talk, I will trace the evolutionary origins of some of the major contemporary clones of S. aureus causing disease in humans and livestock and examine their spatial and temporal dynamics. In addition I will discuss insights into the role of horizontal gene transfer, and mutation in the ability of S. aureus to adapt to different niches after a host-switch event and dissect some of the mechanisms involved. Finally, I will explore the idea that some S. aureus lineages have greater potential to cross the species barrier and cause zoonotic or anthroponotic disease.