| Summary: | <i>Staphylococcus aureus</i> is a wide-spread human pathogen, and one of the top causative agents of nosocomial infections. The prevalence of antibiotic-resistant <i>S. aureus</i> strains, which are associated with higher mortality and morbidity rates than antibiotic-susceptible strains, is increasing around the world. Vaccination would be an effective preventive measure against <i>S. aureus</i> infection, but to date, every vaccine developed has failed in clinical trials, despite inducing robust antibody responses. These results suggest that induction of humoral immunity does not suffice to confer protection against the infection. Evidence from studies in murine models and in patients with immune defects support a role of T cell-mediated immunity in protective responses against <i>S. aureus</i>. Here, we review the current understanding of the mechanisms underlying adaptive immunity to <i>S. aureus</i> infections and discuss these findings in light of the recent <i>S. aureus</i> vaccine trial failures. We make the case for the need to develop anti-<i>S. aureus</i> vaccines that can specifically elicit robust and durable protective memory T cell subsets.
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