Staphylococcus aureus bacteraemia is a common and important infection resulting in significant morbidity and mortality irrespective of whether the bacteraemia is acquired in the community or in the hospital setting. Mortality remains high with approximately one third of patients dying within 30 days of their bacteraemic episode. These outcomes likely reflect a complex interplay between pathogen and host with medical management including antibiotic therapy able to augment these interactions to varying degrees. The most consistent predictor of mortality is age, with older patients twice as likely to die compared to younger adults. Except for the presence of certain co-morbidities, the impact of other host factors remains unclear. Host-Pathogen interactions as manifested by the severity of illness similarly predict outcomes. Source or location of bacteremic acquisition does not impact on patient outcomes despite a close association with the infecting Staphylococcus aureus clone. Other pathogen variables are inconsistently associated with mortality with the exception of antibiotic resistance. Controversy exists however, whether this measured antimicrobial resistance is a surrogate for altered pathogen specific factors or equates to antibiotic failure. Irrespective of these complexities, the treating clinician is only able to influence a limited number of variables with antibiotic therapy the most significant factor. Thus understanding the link between resistance and possible therapeutic failure would result in better patient management and possible outcomes. The broad objective of my PhD is to therefore to better understand the relative role that reduced vancomycin susceptibility plays in S. aureus bacteraemia mortality and the subsequent implications for antimicrobial therapy. More specifically, my aims include 1) to determine the impact of reduced vancomycin susceptibility relative to other factors in S. aureus bacteraemia mortality, 2) to review definitions, establish optimal laboratory testing methodologies and determine the prevalence of reduced vancomycin susceptible infections, 3) to establish whether the likelihood of mortality is increased with these infections, and 4) to review the need to substitute vancomycin with alternative therapies when treating these infections. These aims are examined over 5 chapters with the majority of work presented as published works.