Before the antibiotic era of medicine began about 50 years ago, the prognosis for patients with severe staphylococcal infections was extremely poor. In the early 1940s, the introduction of penicillin G (PCG) temporarily solved the problem of staphylococcal infections, but the continued use of this agent caused the selection of resistant strains, which produced penicillinase. Accordingly, the value of PCG had seriously reduced by 1948. By then S. aureus had acquired multiple resistance to virtually all available systemic antibiotics, including aminoglycosides, tetracycline, chloramphenicol and the macrolides. The introduction of the semisynthetic penicillinase resistant penicillins (e.g., methicillin, oxacillin) and the 1st generation cephems brought about a general decline in the prevalence of multiply resistant S. aureus during the early 1960s. The strains of methicillin-resistant S. aureus (MRSA) were initially detected in 1961 in the United Kingdom, shortly after methicillin came into clinical use, and they have subsequently been isolated in many other parts of the world including Japan. In Japan, most strains of MRSA now represent high level resistance to all antibiotics, except for a few antibiotics, such as vancomycin and arbekacin, and therefore, they posed a serious problem clinically and epidemiologically, via immuno-suppressed inpatients, in particular, as the causative pathogen of nosocomial infection. The appearance and spread of such MRSA strains in Japan may be due to the extensive use of broad spectrum antibiotics, particularly the 3th generation cephems. It is now important to reconsider the modern chemotherapy which evoke serious drug-resistant mutants, such as MRSA.