Since the introduction of penicillin G into practical use in 1940s, Staphylococcus aureus has always outwitted our repeated attempts to eradicate it. Now, S. aureus has become a symbol of our unattainable dream of anti-infective chemotherapy. Not only in the hospital but also in the community, methicillin-resistant S. aureus (MRSA), the historical stumbling block of our efforts, is still causing trouble after its first isolation in 1960, and showing no sign of decline in the future to come. Why is the organism so flexible and tenacious? Thanks to the development of high-throughput sequencing technologies, we have started to take a glimpse of the secret how the organism has conquered our “silver bullets” developed in the last century. It was a memorable experience for us to have uncovered the genomic structure of S. aureus in 2001, and have witnessed how skillfully and dramatically it could change its genetic traits in adverse environment. We now recognize that staphylococcal cassette chromosome (SCC), as an efficient interspecies transfer system of genetic information, has greatly contributed to the evolution of MRSA. Another secret of flexibility of S. aureus genome comes from its versatile regulatory system. Incorporation of point-mutations in the regulatory genes is responsible for the vancomycin resistance of vancomycin-intermediate S. aureus (VISA) strains. These ‘regulator mutations’ seem to protect the cell by altering its physiology and preventing the access of the antibiotics to their targets of action. I shall explain recent advances in our genomic study on the evolutionary potential of S. aureus, which would give us an insight into our future strategy to treat this amazing organism.