Staphylococcus aureus, an important bacterial pathogen in the hospital and the community, has become increasingly resistant to multiple antibiotics. Non-antimicrobial approaches to controlling S. aureus are clearly needed. Because many individuals who are susceptible to staphylococcal infections are not competent to mount an effective immune response, passive as well as active immunisation strategies have been explored. A capsular polysaccharide-based vaccine (StaphVAX) showed promise in an initial phase III trial in haemodialysis patients, but was found to be ineffective in a confirmatory trial. Likewise, a human immunoglobulin G (IgG) preparation known as INH-A21 (Veronate) with elevated levels of antibodies to the staphylococcal surface adhesins ClfA and SdrG made it into phase III testing, where it failed to show a clinical benefit in neonates. A number of novel antigens are in pre-clinical trials, including cell-wall-anchored adhesins, surface polysaccharides and exotoxoids. Given the multiple and sometimes redundant virulence factors of S. aureus that enable it to be such a crafty pathogen, if a vaccine is to prove effective it will of necessity be multicomponent, incorporating a number of surface proteins, toxoids and surface polysaccharides.