Mupirocin was introduced into clinical practice in the UK in 1985, and has proved to be an extremely effective treatment of skin infections and one of the most successful topical antibiotics for the clearance of nasal Staphylococcus aureus isolates including those resistant to methicillin. It is currently registered for use in more than 90 countries worldwide. Unfortunately resistance was described shortly after its initial use. Many of the issues regarding its use are reviewed here, together with the mechanisms, genetics, surveillance and epidemiology of resistance, particularly in staphylococci. The various factors that increase resistance and how they might be controlled are also discussed.