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Low-level vancomycin resistance in Staphylococcus aureus has emerged as a clinical problem over the past 8 years. The clinical relevance of this resistance has been questioned, and laboratory detection remains difficult and time consuming. There is, however, increasing evidence linking low-level vancomycin resistance with glycopeptide treatment failure in serious Staphylococcus aureus infections. Diagnostic laboratories and clinicians need to be aware of this resistance phenotype, to have procedures in place to detect the resistance, and to have strategies for managing patients with infections caused by resistant strains.