The skin is positioned at the interface between an organism's internal milieu and an external environment characterized by constant assault with potential microbial pathogens. While the skin was formerly considered an inactive physical protective barrier that participates in host immune defense merely by blocking entry of microbial pathogens, it is now apparent that a major role of the skin is to defend the body by rapidly mounting an innate immune response to injury and microbial insult. In the skin, both resident and infiltrating cells synthesize and secrete small peptides that demonstrate broad-spectrum antimicrobial activity against bacteria, fungi, and enveloped viruses. Antimicrobial peptides also act as multifunctional immune effectors by stimulating cytokine and chemokine production, angiogenesis, and wound healing. Cathelicidins and defensins comprise two major families of skin-derived antimicrobial peptides, although numerous others have been described. Many such immune defense molecules are currently being developed therapeutically in an attempt to combat growing bacterial resistance to conventional antibiotics.