The effective management of complicated Staphylococcus aureus bacteremia and native valve endocarditis requires an appropriate course of antimicrobial agents (proper agent, duration, and dose) and, where possible, timely removal of foci of infection. Treatment options for methicillin-susceptible S. aureus (MSSA) bacteremia, methicillin-resistant S. aureus (MRSA) bacteremia, and MRSA complications are discussed. The use of vancomycin for the treatment of MRSA bacteremia and the challenges associated with its use are described (ie, decreased susceptibility, emergence of heteroresistant vancomycin-intermediate S. aureus [hVISA] isolates, and nephrotoxicity). The use of aminoglycosides or rifampin as adjunct therapy with vancomycin to treat S. aureus bacteremia does not appear to be supported by data in the medical literature. The optimal length of therapy for S. aureus infections is presented, and the need for periodic reassessment of vancomycin and daptomycin minimum inhibitory concentrations (MICs) is emphasized. The author suggests an approach to treatment of persistent MRSA bacteremia based on recent data.