High attack rates and the ability of Staphylococcus aureus to develop resistance to all antibiotics in medical practice heightens the urgency for vaccine development. S. aureus causes many disease syndromes, including invasive disease, pneumonia, and skin and soft tissue infections. It remains unclear whether a single vaccine could protect against all of these. Vaccine composition is also challenging. Active immunization with conjugated types 5 and 8 capsular polysaccharides, an iron scavenging protein, isdB, and passive immunization against clumping factor A and lipoteichoic acid have all proven unsuccessful in clinical trials. Many experts advocate an approach using multiple antigens and have suggested that the right combination of antigens has not yet been identified. Others advocate that a successful vaccine will require antigens that work by multiple immunologic mechanisms. Targeting staphylococcal protein A and stimulating the T-helper 17 lymphocyte pathway have each received recent attention as alternative approaches to vaccination in addition to the more traditional identification of opsonophagocytic antibodies. Many questions remain as to how to successfully formulate a successful vaccine and to whom it should be deployed.