Most of the defensive functions of the human skin are localized to the stratum corneum (SC), the outermost layer of the epidermis consisting of several layers of cornified keratinocytes embedded in a lipid matrix. Included in the armamentarium of the epidermal barrier against microbial invasion are surface pH, SC lipids, specialized antimicrobial peptides such as defensins and cathelicidins, enzymes and enzyme inhibitors, chemokines, and epidermal Toll-like receptors. Multiple epidermal defensive mechanisms are co-localized, coregulated, and intertwined. The purpose of this review is to discuss patents and to describe the current knowledge that concerns the role of the epidermis as an antimicrobial barrier, outlining potential clinical and therapeutic implications.