Skin is an active immune organ, which protects the human internal organs from biotic and abiotic hazards. Staphylococcus epidermidis is a primary bacterial colonizer of the skin and one of the most abundant microorganisms among the other skin microbiome. Moreover, this bacterial sp. is considered as an active microbiological barrier of the skin and one of its defensive components. On the other side, S. epidermidis is a causative agent of serious infections including wound infections, and bacteremia. The aims of the current mini-review were to attract the attention of the scientific community to this perplexing bacterium, and to develop an enhanced understanding about the role of this microorganism in the skin. Furthermore, it is necessary to understand the relationship between the protective mechanisms of this bacterium in the human skin, and to realize the influences that direct this bacterium to turn from a useful commensal to a serious contagion.