Staphylococcus aureus remains a leading cause of health care-associated infection. Although methicillin-resistant S aureus (MRSA) has declined in many high-income settings, methicillin-susceptible S aureus (MSSA) continues to cause many invasive infections. Thus, infection control programs only focused on MRSA have now become obsolete. Considering also that MRSA spread is mainly exogenous and MSSA infection often arises from endogenous carriage, this article attempts to synthesize evidence for horizontal (non-pathogen-specific) strategies-hand and environmental hygiene, device care, universal decolonization in high-risk units, optimized surgical prophylaxis-and vertical (targeted) measures such as targeted MRSA/MSSA screening and decolonization.