The health threat posed by Staphylococcus aureus infections urgently necessitates the development of a prophylactic vaccine. Despite significant efforts, effective vaccines remain elusive. A critical bottleneck continues to be the lack of established correlates of immune protection. It is now accepted that effective vaccines will be required to drive cellular as well as humoral immunity. However, efforts to target T cells have yet to deliver convincing results, indicating that we have further to go to understand how to harness appropriate correlates of immunity through vaccination. A significant challenge for S. aureus vaccine development is the requirement to induce protective immunity in a host that is not immunologically naïve. It is increasingly apparent that pre-existing anti–S. aureus immunity may result in significant vaccine interference. In contrast to its reputation as an invasive pathogen, S. aureus is also an important component of the human microbiome, where it primarily colonises the anterior nares. We have discovered that S. aureus drives local immunosuppressive responses during colonisation to promote its own persistence. Overall, however, we have limited appreciation of the immune consequences of exposure to S. aureus as a commensal microbe, or how this exposure might influence subsequent responses to vaccination and/or invasive infection. Our research is focused on understanding the immune imprint established by asymptomatic S. aureus colonisation, with a view to determining how this imprint could be modulated to deliver effective anti–S. aureus vaccines.