Colonization with Staphylococcus aureus is a risk factor for invasive S. aureus infections. Intranasal mupirocin has effectively eradicated S. aureus colonization and appears to prevent S. aureus nosocomial infections in some patient populations. In hospitals and communities where mupirocin use has been widespread, resistance to the drug has emerged. New strategies and agents are needed if we want to significantly decrease the risk of S. aureus infections.