S. aureus infective endocarditis (SAIE) is a serious infection associated with considerable morbidity and mortality. There is evidence that the incidence of SAIE is increasing. As its clinical features are non-specific, SAIE must be suspected in every case of S. aureus bacteraemia, whether it is associated with an obvious source or not. The optimal antimicrobial agent(s) and duration of treatment for SAIE are currently not known, but on the basis of present evidence, a minimum of 2 weeks of antimicrobial therapy is recommended for 'right-sided' SAIE, a minimum of 4 weeks for uncomplicated 'left-sided' SAIE, and a minimum of 6 weeks for complicated 'leftsided' or prosthetic valve SAIE. Although there is no evidence to suggest that combination therapy with a cell-wall active agent (e.g. flucloxacillin) and an aminoglycoside decreases mortality in SAIE, combination therapy should be considered during the initial 3-5 days of therapy as it can shorten the duration of bacteraemia. In complicated or prosthetic valve SAIE, early and close liaison with cardiology and cardiothoracic surgery services is essential. Rapid identification and susceptibility testing of the infecting organism are important in determining the choice of definitive antimicrobial therapy.