Staphylococcus aureus is an important cause of nosocomial and community-acquired infections in humans and animals, as well as mastitis in dairy cattle. Methicillin-resistant S. aureus is increasingly recognized as a cause of staphylococcal infection and, therefore, immunotherapeutics have received new interest in both human and veterinary medicine. Vaccines aimed at preventing S. aureus infection in humans and mastitis in dairy cattle have been studied for many years. While some formulations have shown promise in ameliorating clinical disease, few, if any, of the S. aureus vaccines developed have adequately prevented new infection. The antigens targeted by S. aureus vaccines and potential reasons for the lack of success of vaccination against S. aureus are reviewed in this article.