Staphylococcal infective endocarditis is a severe event requiring aggressive therapy. Antibiotic regimen depends mainly on (1) the species of Staphylococcus (Staphylococcus aureus versus coagulase-negative staphylococci) and its resistance pattern (resistance to penicillin, to methicillin, to multiple classes of antibiotics); (2) the type of infected valve (native versus prosthetic); (3) the site of infection (left side versus right side endocarditis); (4) some underlying conditions of the host, in particular the presence or not of intravenous drug abuse. Based on in vitro susceptibility results, animal models and clinical trials, the following regimens are currently recommended. For native valve endocarditis, penicillin G 20 million units per day i.v. for 4-6 weeks for penicillin-susceptible strains; a penicillinase-resistant penicillin (oxacillin) 2 g i.v. q 4 h for 4-6 weeks plus an aminoglycoside (gentamicin) 1.0 mg.kg-1 i.v. q 8 h for 1 week, for penicillin-resistant, methicillin-susceptible strains; for methicillin resistant strains, vancomycin 30 mg.kg.day-1 i.v. in 2-4 doses for 4-6 weeks with the addition or not of rifampin 600-900 mg.day-1 orally. For a prosthetic valve endocarditis, a three-drug regimen (oxacillin or vancomycin, plus gentamicin and rifampin) and a longer duration (6 weeks or more) are generally recommended. Shorter (2 weeks) treatment could be delivered to uncomplicated cases of right-sided endocarditis. In view of an increased resistance to classic drugs and suboptimal efficacy of some of them, new therapeutic modalities should be looked at, in particular for endocarditis cases due to methicillin-resistant strains.