Recent emergence of vancomycin resistance in methicillin-resistant Staphylococcus aureus (VRSA) has posed a new threat to hospital infection control and antibiotic chemotherapy. Relatively low-level resistance of VRSA compared to that of vancomycin-resistant enterococci (VRE), and prevalence of S. aureus clinical strains heterogeneously resistant to vancomycin (hetero-VRSA), challenge the value of routine antibiotic susceptibility tests as a tool for the prediction of clinical efficacy of vancomycin therapy. This review summarizes the history of emergence of glycopeptide resistance in staphylococci and considers the mechanism of resistance in these organisms.