Since the discovery, development, and US Food and Drug Administration approval of vancomycin in the 1950s, this agent has remained a mainstay for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, because of the development of new antistaphylococcal antibiotics and reports of vancomycin failures, the utility of vancomycin has recently been questioned. Although vancomycin did not undergo the strict US Food and Drug Administration approval process that is in place today to demonstrate efficacy, there is considerable information available that sheds light on the role vancomycin has in infectious diseases pharmacotherapy today. In addition, although we look to in vitro susceptibility testing to assess vancomycin activity against S. aureus, we have come to appreciate that resistance of S. aureus to vancomycin can be a continuous--rather than a categorical--phenomenon. This has resulted in clinical microbiology laboratories having difficulty identifying S. aureus that may not respond to conventional doses of vancomycin. A better understanding is needed of the pharmacodynamic relationship between vancomycin and MRSA as relates to optimal dosing strategies, including consideration for loading doses, and development of rational categorical breakpoints for susceptibility based on clinical outcomes. By better understanding these critical issues, it may be possible to optimize the use of vancomycin, resulting in a cost-effective treatment option for many patients infected with MRSA.