Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major public concern. Hospital-acquired MRSA rates have steadily increased over the past 25 years, and the bacterial strain is making inroads to the community. The morbidity and mortality burden of MRSA infection is compounded by delayed or inappropriate antibiotic treatment, taking a toll on health care resources that are already stretched thin. Vancomycin has historically been the drug of choice for this pathogen because its broad spectrum can address the multidrug resistance of most MRSA infections. Despite its sustained in vitro microbiologic inhibitory activity, researchers are beginning to question the continued utility of vancomycin for MRSA infections. Evidence against vancomycin is most notable with regard to nosocomial pneumonia and skin and soft tissue infections. In addition, because vancomycin must be administered intravenously, patients typically require prolonged hospitalization, which further increases the cost of MRSA treatment and exposes patients to additional nosocomial infections. Recent studies have shown that antibiotics with good bioavailability, such as linezolid, can be given orally to facilitate early hospital discharge, thus alleviating the economic burden of MRSA infections. Several agents have been developed over the past decade that have excellent in vitro activity against MRSA. Further studies are needed to determine if these drugs can better eradicate MRSA than vancomycin and remedy the adverse outcomes frequently observed with this organism.