Perhaps the most valuable lesson we have obtained from analyzing the nucleotides of staphylococcal genomes is that staphylococci can respond to whatever treatment is used against them and therefore will probably never become extinct. They have outlived long catastrophic years on this planet with the impact of our assault on them being merely a ripple similar to that caused by throwing a stone into a pond. To defend themselves from our “silver bullets” they are able to change quickly and efficiently. After our fight with chemotherapy against staphylococci for half a century, it has been a memorable experience to have uncovered their genomic structure in 2001, and subsequently learn how skillfully and dramatically they can change their genetic traits during warfare. We have discovered ingenious genetic devices such as SCCmec, oriC environ, and IS-mediated large-scale recombination of staphylococcal chromosomes, and as a result can now appreciate why our battery of weapons against them are transient and are in vain. With our recent studies on Staphylococcus and Macrococcus genomes, I shall review the evolutionary potential of staphylococci which may give us an insight into treating infections caused by these amazing bacteria.