During the past decade much effort has been devoted worldwide to limiting the spread of methicillin-resistant Staphylococcus aureus. However, the recent emergence of almost untreatable vancomycin-resistant enterococci has led to a new and unexpected public health problem in hospitals and the community. Moreover, the threat of transfer of glycopeptide resistance to S aureus means that development of alternative antimicrobial strategies has become urgent. Whereas major advances have been made in our understanding of methicillin and vancomycin resistance mechanisms, we still need to identify the sources and reservoirs of the genetic determinants of resistance and to discover how they disseminate in the environment. The outcome of the battle between antimicrobials and bacteria is still uncertain, but the challenge is worth meeting.