The skin actively contributes to host defense by mounting an innate immune response that includes the production of antimicrobial peptides. These peptides, which include but are not limited to the cathelicidin and defensin gene families, provide rapid, broad-spectrum defense against infection by acting as natural antibiotics and by participating in host cell processes involved in immune defense. This review discusses the biology and clinical relevance of antimicrobial peptides expressed in the skin. The importance of the epithelial contribution to host immunity is evident, as alterations in antimicrobial peptide expression have been associated with various pathologic processes.