Host defenses at the mucosal surface of the airways evolved to present many layers of protection against inhaled microbes. Normally, the intrapulmonary airways are sterile. Airway secretions contain numerous factors with antimicrobial activity that contribute to innate defenses. Many protein and peptide components exert bacteriostatic or bacteriocidal effects against a wide variety of organisms and may act in synergistic or additive combinations. The beta-defensins are a relatively recently described family of peptide antimicrobials that are widely expressed at mucosal surfaces, including airway and submucosal gland epithelia. These small cationic peptides are products of individual genes that exhibit broad-spectrum activity against bacteria, fungi, and some enveloped viruses. Their expression in airway epithelia may be constitutive or inducible by bacterial products or pro-inflammatory cytokines. beta-defensins also act as chemokines for adaptive immune cells, including immature dendritic cells and T cells via the CCR6 receptor, and provide a link between innate and adaptive immunity. Alterations in the function of the beta-defensins may contribute to disease states. Here we review much of the biology of the beta-defensins, including gene discovery, genomic organization, molecular structure, regulation of expression, and function.