Staphylococcus aureus is a leading cause of human bacterial infection, most notable for its ability to infect any tissue in the human host. Among the most common sites of S aureus infection is the skin, predicated by the existence of this organism as a part of the commensal flora in up to half of the population. While the molecular mechanisms by which S aureus adapts to the ecologic niche of the skin and transitions to cause both skin infection and more severe invasive disease are incompletely defined, these represent an exciting and rapidly moving area of research. The ultimate goal of these investigations is to understand human disease pathogenesis, define host susceptibility factors that predispose to colonization and infection, and utilize this knowledge to inform the strategic development of novel preventive and therapeutic strategies.