Staphylococcus aureus causes hospital-acquired (HA), community-acquired (CA) and companion animal and livestock-associated (LA) infections. Molecular epidemiology studies suggest that although host speciicity may be associated with speciic genetic lineages, recent human-to-animal and animal-to-human transmissions related to mobile genetic elements have been described. Gene transfers include virulence and antibiotic resistance genes, thus making it diicult to control multidrug resistance S. aureus infections. Bacteriophages (phages) and endolysins, the enzymes responsible for bacterial lysis by phages, are alternatives to the use of antibiotics for the control of S. aureus infections. In this work, we review current advances in the development of phage therapy and the study and design of recombinant endolysins to treat S. aureus infections. Preliminary results of bacteriophage isolation based on molecular epidemiology knowledge show that bacteriophages are speciic of genetic lineages and that this strategy may be used as an approach to isolate and evaluate new bacteriophages for therapy.