Staphylococcus aureus is a major global pathogen. In addition to a wide spectrum of human diseases, S. aureus causes economically important infections of cows, sheep, poultry, and rabbits. We have been investigating the evolutionary history of S. aureus clones associated with different host species and the molecular basis for host-adaptation. Using a high resolution phylogenetic approach, we have identified ancient and recent host-switching events leading to the emergence of endemic clones in both humans and livestock. In addition, comparative genomic analysis has resulted in the identification of specific mutations and mobile genetic elements which have contributed to the capacity to infect different host species. Bacterial determinants required for host-specificity could represent novel therapeutic targets for controlling human and animal infections. In this presentation, I will summarise some of our recent findings relating to the dynamics and mechanics of S. aureus host-adaptation.