Strains of Methicillin-resistant Staphylococcus aureus (MRSA) are a major cause of hospital-acquired infections worldwide and are responsible for significant morbidity and mortality; MRSA accounts for approximately 24% of S. aureus bloodstream infections in Australia. While vancomycin remains the current treatment of choice for such infections, the optimal therapy for failing patients is yet to be defined, and it is in these settings that mutations associated with drug resistance (and other advantageous phenotypes) are likely to emerge. In order to obtain an expanded understanding of within host evolution, particularly in the context of antibiotic exposure, we have sequenced MRSA isolate series from different patients who had persistent/recurrent infections. The first series was obtained from a single patient episode, over a 77-day period, and was comprised of six ST239-MRSA blood culture isolates. The second series was obtained from multiple episodes (from a single patient), over a 19-month period, and was comprised of nine ST105-MRSA isolates associated with different infection types. Lessons learnt will be discussed in context of both evolutionary dynamism and the utility of whole genome sequencing as a diagnostic tool.