Antimicrobial peptides are part of the host defense systems of plants, insects, fish, amphibia, birds, and mammals. These small proteins were previously thought of as an evolutionarily ancient system of immune protection with little relevance to the normal function of human skin. Recent developments have found that mammalian skin expresses these gene-encoded peptide antibiotics during inflammatory events such as wound repair, contact dermatitis, and psoriasis. The presence of these peptides in the skin forms a barrier for innate host protection against microbial pathogenesis. Furthermore, antimicrobial peptides also act on animal cells by stimulating them to change behaviors such as syndecan expression, chemotaxis, and chloride secretion. The combination of effects on host cells with antimicrobial action in a single molecule represents an efficient defense and response system against injury. Understanding the action of antimicrobial peptides in skin may yield further insight into the mechanism of innate cutaneous disease control and provide new approaches to therapy of wounds and inflammatory dermatitis.