The innate immune system is the primary defence against bacterial infection. Among the factors involved in innate defence, anti‐microbial peptides produced by humans have recently attracted attention due to their relevance to some diseases and also to the development of new chemotherapeutic agents. Staphylococcus aureus is one of the major human pathogens, causing a variety of infections from suppurative disease to food poisoning. Methicillin‐resistant S. aureus (MRSA) is a clinical problem and with the recent emergence of a vancomycin‐resistant strain, this will pose serious problems in the near future. In investigating the molecular biology of S. aureus infections to develop new chemotherapeutic agents against MRSA infections, knowledge of the interaction of innate anti‐microbial peptides with S. aureus is important. In vitro and in vivo experiments demonstrate that exposure of S. aureus to host cells can induce the anti‐microbial peptides β‐defensin‐2 (hBD2), hBD3, and LL37/CAP18. The induction level of these peptides differs among strains, as does the susceptibility of the strains, with MRSA strains exhibiting lower susceptibility. In summary, the susceptibility of S. aureus strains, including MRSA strains, to components of the innate immune system varies, with the MRSA strains showing more resistance to both innate immune factors and chemotherapeutic agents. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.