Oral epithelium is a stratified squamous epithelium that functions as the barrier between the outside environment and the host. In the oral cavity, epithelial tissues are constantly exposed to a variety of bacteria, but most individuals maintain healthy homeostasis. Epithelial cells contribute to the innate host response, and antimicrobial peptide expression in all human epithelia, including oral epithelia, is an important part of this epithelial function. These antimicrobial peptides have a broad spectrum of activity against both Gram-negative and Gram-positive bacteria as well as against yeast and viruses. In humans these antimicrobial peptides include defensins and a cathelicidin family member LL-37 in skin and oral mucosa and other epithelia. The human defensins include the alpha-defensins of intestinal and neutrophil origin, and the beta-defensins of skin and oral mucosa and other epithelia. Present studies have identified specific signaling routes that pathogens and commensals take in stimulating these innate immune responses, and this may open the way for development of new therapeutic agents for periodontal diseases.