This review discusses several aspects of vaccine development efforts for Staphylococcus aureus. While several vaccines have shown efficacy in pre-clinical models, a potent and successful S aureus vaccine still eludes us. This review captures the historical literature on S. aureus vaccine development and discusses the results of major clinical trials in the field. Here we discuss important new insights into immunological mechanisms of protection from extracellular bacterial infections and shed light on important pre-clinical and clinical findings that establish a correlation between S. aureus infections and lack of cell mediated immunity. We attempt to provide an immunological explanation for the reasons behind the failure of prior S. aureus vaccines and provide insight into the rational design of a universal vaccine for S. aureus infections.