Staphylococcus aureus is a leading pathogen in surgical site, intensive care unit, and skin infections, as well as healthcare-associated pneumonias. These infections are associated with an enormous burden of morbidity, mortality, and increase of hospital length of stay and patient cost. S. aureus is impressively fast in acquiring antibiotic resistance, and multidrug-resistant strains are a serious threat to human health. Due to resistance or insufficient effectiveness, antibiotics and bundle measures leave a tremendous unmet medical need worldwide. There are no licensed vaccines on the market despite the significant efforts done by public and private initiatives. Indeed, vaccines tested in clinical trials in the last two decades have failed to show efficacy. However, they targeted single antigens and contained no adjuvants and efficacy trials were performed in severely ill subjects. Herein, we provide a comprehensive evaluation of potential target populations for efficacy trials taking into account key factors such as population size, incidence of S. aureus infection, disease outcome, primary endpoints, as well as practical advantages and disadvantages. We describe the whole-blood assay as a potential surrogate of protection, and we show the link between phase III clinical trial data of failed vaccines with their preclinical observations. Finally, we give our perspective on how new vaccine formulations and clinical development approaches may lead to successful S. aureus vaccines.