Serious staphylococcal infections remain a significant clinical problem despite advances in antibacterial therapy. Resistance to penicillin is common and methicillin-resistant staphylococci have become troublesome nosocomial pathogens in many institutions. Penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin and oxacillin) are the preferred drugs for all methicillin-susceptible staphylococcal infections, although first generation cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, clindamycin, and occasionally erythromycin and cotrimoxazole (trimethoprim/sulfamethoxazole) are alternatives. Serious infections due to methicillin-resistant staphylococci should be treated with parenteral vancomycin. Teicoplanin, where available, is a suitable alternative. Rifampicin, fusidic acid and some fluoroquinolones may be useful oral alternatives, although resistance develops rapidly if they are used as single agents. Cotrimoxazole and minocycline have also proven useful when strains are susceptible. Staphylococcal toxic shock syndrome often requires aggressive resuscitation and anti-staphylococcal therapy for generally 10 to 14 days. Staphylococcus aureus bacteraemia remains a life-threatening condition which, in all but one-third of cases, is associated with an underlying septic focus such as endocarditis, osteomyelitis or occult abscess. Differentiating between complicated and uncomplicated bacteraemia is critical to define the appropriate treatment regimen. Serious staphylococcal sepsis such as endocarditis and acute osteomyelitis generally requires prolonged (4 to 6 weeks) antibiotic treatment. Coagulase-negative staphylococci are the commonest cause of prosthetic device infection, and generally require prolonged therapy with an agent to which they have proven to be sensitive, e.g. a penicillinase-resistant penicillin or vancomycin. Removal of infected foreign or prosthetic material, and drainage of deep collections remain a critical aspect of all therapy.