The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalised patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with healthcare. The most rapidly spreading and tenacious healthcare-associated clone in Europe currently is EMRSA-15, a lineage that was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. To understand the genetic events that have accompanied the emergence of the EMRSA-15 pandemic, we obtained genome sequences for 193 isolates that were chosen for their geographical and temporal diversity, and belong to the same multilocus sequence type as EMRSA-15. Using phylogenomic methods, we were able to show that the current pandemic population of EMRSA-15 descends from a healthcare-associated MRSA epidemic that spread through England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 sub-clone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this sub-clone over the last twenty years has grown four times faster than its progenitor. Using comparative genomic analysis we were able to identify the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens.