The efficacy of vancomycin for the treatment of patients with infections due to Staphylococcus aureus is impaired by its poor tissue penetration and by its relatively weak antibacterial activity--an activity that is declining as S. aureus evolves. Neither dose escalation nor use of vancomycin in combination with other antibiotics that have antistaphylcoccal activity has been demonstrated to safely enhance its therapeutic efficacy. Although no clinical trials suggest superiority of vancomycin over any comparator, some have provided evidence of its inferiority. Strong consideration should be given to the use of alternative agents in the treatment of serious S. aureus infections.