Vancomycin has been the most reliable therapeutic agent against infections caused by meticillin-resistant Staphylococcus aureus (MRSA). However, in 1996 the first MRSA to acquire resistance to vancomycin, was isolated from a Japanese patient. The patient had contracted a post-operative wound infection that was refractory to long-term vancomycin therapy. Subsequent isolation of several vancomycin resistant S. aureus (VRSA) strains from USA, France, Korea, South Africa, and Brazil has confirmed that emergence of vancomycin resistance in S aureus is a global issue. A certain group of S. aureus, designated hetero-VRSA, frequently generate VRSA upon exposure to vancomycin, and are associated with infections that are potentially refractory to vancomycin therapy. Presence of hetero-VRSA may be an important indicator of the insidious decline of the clinical effectiveness of vancomycin in the hospitals. Vancomycin resistance is acquired by mutation and thickening of cell wall due to accumulation of excess amounts of peptidoglycan. This seems to be a common resistance mechanism for all VRSA strains isolated in the world so far.