The staphylococci have been recognized as serious pathogens for over a century and are the etiological agent of a variety of diseases ranging from mild cutaneous infections to often fatal forms of septic arthritis, endocarditis, toxic shock syndrome and sepsis. Despite intensive efforts to halt their spread, they remain the most common cause of community- and nosocomially acquired bacteremia. Murine models of Staphylocococus aureus-mediated arthritis and sepsis exist and are being used to gain a better understanding of the host-bacterium relationship as well to develop better methods of prevention and treatment.