Following the discovery in 1992 that resistance to vancomycin could be transferred in vitro from a strain of Staphylococcus haemolyticus to Staphylococcus aureus, the threat that a similar event could happen in vivo has existed. In 1996, the threat became a reality in Japan followed by reports of low-level heteroresistant S. aureus from elsewhere in the world. However, the threat has not gone away; indeed it has become more intimidating within the past 2 years with the isolation of higher-level resistance to vancomycin transferred on a plasmid from Enterococcus faecalis. The mechanisms of resistance are different in each of the types of S. aureus with reduced susceptibility to the glycopeptides: in one hetero-vancomycin intermediate-susceptible S. aureus (hVISA) and vancomycin intermediate-susceptible S. aureus (VISA), cell wall biosynthesis is altered, hindering glycopeptide reaching its target, and in the other vancomycin-resistant S. aureus (VRSA) the target is altered. This review attempts to place into context the threat posed to patients by the appearance of strains of S. aureus more resistant to one of the key therapeutic agents used in our hospitals. It will do so by raising a number of important questions followed by the presentation of experimental evidence that may or may not provide answers that heighten or lower the threat.