While nosocomial infections by Staphylococcus epidermidis have gained much attention, this skin colonizer has apparently not evolved to cause disease, but maintain the commonly benign relationship with its host. Accordingly, S. epidermidis does not produce aggressive virulence determinants. Rather, factors that normally sustain the commensal lifestyle of S. epidermidis seem to rise to additional benefit during infection. Furthermore, we are beginning to comprehend the roles of S. epidermidis in balancing the epithelial microflora and serving as a reservoir of resistance genes. In this review, the molecular basis of the commensal and infectious lifestyles of S. epidermidis will be discussed.