The treatment of methicillin-resistant Staphylcoccus aureus (MRSA) infections is one of the most difficult tasks faced by clinicians of present time. Glycopeptides such as vancomycin have served as the cornerstones of therapy against serious MRSA infections. However, resistance to glycopeptides in S. aureus has emerged within the past decade and the mechanism of resistance in glycopeptide intermediate S. aureus (GISA) remains poorly understood. This article focuses on properties of GISA in the context of changes in global regulator function and the consequences of these changes not only on resistance to glycopeptides but also on resistance to other molecules and on the pathogenesis of the organism.