Staphylococcus aureus infections are associated with increased morbidity, mortality, hospital stay, and health care costs. S aureus colonization has been shown to increase risk for invasive and noninvasive infections. Decolonization of S aureus has been evaluated in multiple patient settings as a possible strategy to decrease the risk of S aureus transmission and infection. In this article, we review the recent literature on S aureus decolonization in surgical patients, patients with recurrent skin and soft tissue infections, critically ill patients, hospitalized non–critically ill patients, dialysis patients, and nursing home residents to inform clinical practice.