Methicillin-resistant Staphylococcus aureus infections are becoming more frequent and less easily treated by means of currently recommended agents. Vancomycin has been associated with decreased susceptibility in staphylococci and with treatment failures. Daptomycin is rapidly bactericidal; a dosage of 4 mg/kg daily is approved for treatment of skin and soft-tissue infections, and a dosage of 6 mg/kg daily is approved for treatment of patients with S. aureus bacteremia and right-sided endocarditis. Findings of in vitro studies suggest a correlation between the minimum inhibitory concentrations of daptomycin and vancomycin. Clinical failure was associated with increasing minimum inhibitory concentrations in case reports and in a randomized study of persons with S. aureus bacteremia and endocarditis. Patients who did not respond to therapy had deep-seated infections that required but could not be or were not managed with adjunctive surgical therapy. No definitive resistance mechanism has been identified, although genetic mutations have been described. Clinically, prior vancomycin therapy has not been associated with failure of daptomycin therapy. Although clinical practitioners must monitor for daptomycin resistance, the available data support the use of daptomycin in the treatment of methicillin-resistant S. aureus bacteremia and endocarditis.