Methicillin-resistant Staphylococcus aureus (MRSA) blood stream infection (BSI) is a major healthcare burden in some but not all healthcare settings, and it is associated with 10%-20% mortality. The introduction of mandatory reporting in England of MRSA BSI in 2001 was followed in 2004 by the setting of target reductions for all National Health Service hospitals. The original national target of a 50% reduction in MRSA BSI was considered by many experts to be unattainable, and yet this goal has been far exceeded (∼80% reduction with rates still declining). The transformation from endemic to sporadic MRSA BSI involved the implementation of serial national infection prevention directives, and the deployment of expert improvement teams in organizations failed to meet their improvement trajectory targets. We describe and appraise the components of the major public health infection prevention campaign that yielded major reductions in MRSA infection. There are important lessons and opportunities for other healthcare systems where MRSA infection remains endemic.