Defensins and related antimicrobial peptides serve a central role in innate immunity in all species of plants and animals. In humans, defensins are widely expressed, including in neutrophils, skin, and mucosal epithelia. Most defensins are potent antibiotics, and some have chemotactic and toxin-neutralizing activities. Results of recent studies on the homeostatic and disease-fighting activities of human defensins point to a key relevance in several pediatric disorders. Inherited variation in defensin gene expression may contribute to susceptibility to several diseases, including psoriasis and Crohn disease. We review here the recent discoveries in innate immunity that shed light on the potential roles of defensins, and other antimicrobial molecules, in the pathophysiology of common pediatric diseases such as atopic dermatitis, necrotizing enterocolitis, cystic fibrosis, and otitis media.