The recognition of the shortcomings of vancomycin as an antistaphylococcal agent, together with the burgeoning availability of alternative effective antistaphylococcal antibiotics, has led to a reassessment of the role of this glycopeptide antimicrobial in clinical therapeutics. Evidence indicates that vancomycin is inferior to semisynthetic penicillins in the treatment of infections due to methicillin-susceptible Staphylococcus aureus. Additional evidence suggests that vancomycin may be inferior to some comparator agents in the treatment of infections due to methicillin-resistant S. aureus (MRSA). While high-level resistance remains rare, data from some centers suggest an evolutionary change in S. aureus, evidenced by reduced susceptibility to vancomycin. This, together with the problem of heteroresistance to vancomycin, as well as poor tissue penetration after its systemic administration, presents potential obstacles to the successful therapy of S. aureus infections with this glycopeptide. While it has been suggested that these problems may be overcome by administration of vancomycin in much higher doses, the efficacy and safety of this approach remains to be determined and will require randomized clinical trials for its demonstration. A number of novel agents with activity against MRSA have been introduced to clinical practice in the last 2 years and others are still in the investigational stage. Despite the fact that these newer agents have been compared with vancomycin in trials only designed to demonstrate noninferiority, some potential evidence of superiority over vancomycin has emerged. While the relative roles of each of these newer agents and vancomycin can only be determined definitively by performance of adequately powered randomized clinical trials, current evidence suggests that vancomycin may be an inferior therapeutic agent.