Staphylococcus aureus is an important pathogen in the hospital and in the community, and it is increasingly resistant to multiple antibiotics. A nonantimicrobial approach to controlling S aureus is needed. The most extensively tested vaccine against S aureus, which is a capsular polysaccharide-based vaccine known as StaphVAX, showed promise in an initial phase 3 trial, but was found to be ineffective in a confirmatory trial, leading to its development being halted. Likewise, a human IgG preparation known as INH-A21 (Veronate) with elevated levels of antibodies to the staphylococcal surface adhesins ClfA and SdrG made it into phase 3 testing, where it failed to show a clinical benefit. Several novel antigens are being tested for potential inclusion in a staphylococcal vaccine, including cell wall-anchored adhesin proteins and exotoxins. 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 have to be multicomponent, incorporating several surface proteins, toxoids, and surface polysaccharides.