Staphylococcal infections represent an enormous burden to the public health system in the US and worldwide. While traditionally restricted to the hospital setting, highly virulent strains have recently emerged that may cause severe, even fatal, disease in healthy adults outside healthcare settings. This situation, together with the increasing resistance to many antibacterials in a wide variety of staphylococcal strains, requires that vaccine development for staphylococcal diseases be re-evaluated. Finding a vaccine for staphylococci is not trivial, as protective immunity to staphylococcal infections does not appear to exist at a significant degree, which may be partly due to the fact that our immune system is in constant contact with staphylococcal antigens and many strains are commensal organisms on human epithelia. Furthermore, the most virulent species, Staphylococcus aureus, produces protein A, a powerful means to evade acquired host defense. While two high-profile vaccine preparations have failed clinical trials within the last few years, promising results from novel approaches based on the combination of systematically selected antigens have been reported. These combinatory vaccines target microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), a family of bacterial proteins that bind to human extracellular matrix components. In addition, polysaccharide and other nonprotein antigens may represent suitable vaccine targets on the staphylococcal cell surface.