Staphylococcal infections continue to be among the most common infections. Methicillin resistance is a common phenomenon, particularly among nosocomial Staphylococcus aureus and coagulase-negative staphylococci. Although wide variations are observed between countries or cities, methicillin resistance is often associated with multiresistance, which includes resistance to rifampicin and fluoroquinolones. In areas where methicillin resistance is common, glycopeptides (vancomycin or teicoplanin) represent the first-line treatment. For both drugs, attention should be paid to appropriate doses and dosing regimens and to the control of serum levels. In septicaemia and endocarditis developed on native valves, the benefit of a combination with an aminoglycoside or any other agent has not been clearly established. Animal studies suggest that combination therapy with a quinolone or rifampicin should be considered, particularly in infections involving foreign bodies. In CNS infections, combinations such as cefotaxime plus fosfomycin, or rifampicin plus a fluoroquinolone can be used. Multiple resistance, however, may limit the efficacy of such combinations. In areas where methicillin resistance is less common, initial therapy can be cefamandole with or without an aminoglycoside, or rifampicin plus a fluoroquinolone. Whatever the treatment, careful evaluation of the clinical response 48 h after initiation of therapy is required.