This review considers the reasons why the staphylococcal vaccine trials may have failed, based on new information about protective immunity against Staphylococcus aureus. The clinical trials and future vaccine candidate antigens are reviewed. Challenges facing the development of a universal S. aureus vaccine are also considered. The lack of a biomarker that is able to predict protection is a major stumbling block in the development of a staphylococcal vaccine. The major new information involves the role of cell-mediated immunity, specifically T-helper 17 cells and interleukin 17, as well as the lack of protection afforded by specific antibodies. This has major implications for future vaccine development and planning of clinical trials.