The incidence of infective endocarditis (IE) is thought to be around 4/100,000 person years in the general population, and 15/100,000 over the age of 50 years. The risk of acquiring IE is higher among patients with valvular heart disease (e.g., rheumatic valves, bicuspid aortic valves, myxomatous degeneration, etc.), congenital heart disease (e.g., coarctation, patent ductus arteriosus, ventricular septal defect, etc.), prosthetic cardiac valves, and among intravenous drug abusers. Staphylococcus aureus is one of the most common infective agents of IE, and most commonly originates from nosocomial sources, e.g., intravenous and arterial catheters, pacemaker leads, and prosthetic valves. Endocarditis caused by S aureus has a mortality rate of approximately 20% to 40%. In up to 40% of patients, IE caused by S aureus is associated with embolic complications. The risk of death increases with the development of complications. The epidemiology and microbiology of S aureus are changing rapidly, and resistance to antibiotics, especially methicillin, is becoming more widespread. In this review we will focus on the epidemiology, microbiology, and pathogenesis of S aureus IE, and also summarize the current guidelines for diagnosis, treatment, and prophylaxis of this clinical condition.