Methicillin-resistant Staphylococcus aureus (MRSA) epidemics, a major cause of healthcare-associated infection, have been caused by a limited number of clones. The epidemic MRSA-15 (EMRSA-15) clone has been found primarily in hospital settings and has been associated with rapid spread over the past two decades. Matthew Holden and colleagues now report whole-genome sequencing and phylogenomic analysis of 193 ST22 isolates (EMRSA-15 clones are included within this MLST) collected from both hospital and community settings within 15 countries from 1990 to 2009, representing a wide geographic and temporal diversity. (Genome Res., published online 8 January 2013; doi:10.1101/gr.147710.112). Their analyses allow tracing of the origins and spread of this epidemic clone, which was first observed in the UK in the 1980s and spread rapidly through the UK, Europe, Asia and Africa. They were able to explain observed resistance phenotypes on the basis of known resistance-conferring mutations for >99% of those tested. They found a stepwise evolution of resistance and show a strong selective pressure exerted by specific commonly used antibiotics. They identified two nonsynonymous SNPs associated with the acquisition of fluoroquinolone resistance within an EMRSA-15 clade in the UK in the mid-1980s, which seems to be associated with an early epidemic spread.