Staphylococcus aureus is a major cause of bacteremia, and S. aureus bacteremia is associated with higher morbidity and mortality, compared with bacteremia caused by other pathogens. The burden of S. aureus bacteremia, particularly methicillin-resistant S. aureus bacteremia, in terms of cost and resource use is high. The risk of infective endocarditis and of seeding to other metastatic foci increases the risk of mortality and raises the stakes for early, appropriate treatment. The incidence of S. aureus bacteremia and its complications has increased sharply in recent years because of the increased frequency of invasive procedures, increased numbers of immunocompromised patients, and increased resistance of S. aureus strains to available antibiotics. This changing epidemiology of S. aureus bacteremia, in combination with the inherent virulence of the pathogen, is driving an urgent need for improved strategies and better antibiotics to prevent and treat S. aureus bacteremia and its complications.