Bacteremia and infective endocarditis (IE) are important causes of morbidity and mortality associated with Staphylococcus aureus infections. Increasing exposure to healthcare, invasive procedures, and prosthetic implants has been associated with a rising incidence of S. aureus bacteremia (SAB) and IE since the late twentieth century. S. aureus is now the most common cause of bacteremia and IE in industrialized nations worldwide and is associated with excess mortality when compared to other pathogens. Central tenets of management include identification of complicated bacteremia, eradicating foci of infection, and, for many, prolonged antimicrobial therapy. Evolving multidrug resistance and limited therapeutic options highlight the many unanswered clinical questions and urgent need for further high-quality clinical research.