Allergy in its various manifestations is a systems disease consisting of networks among multiple organs. The epithelium plays a central role in allergic disorders, and allergic sensitization occurs through the skin unless tolerance is induced through the gastrointestinal tract. Filaggrin loss-of-function mutations result in impaired epithelial barrier integrity and are substantial genetic risk factors for atopic dermatitis, asthma, allergic rhinitis, and food allergy in children. Dysregulated growth and repair pathways and interplay between airway epithelium asthma gene loci and viral, allergen, or microbial exposure are substantial factors for early-onset asthma development and exacerbation. As a critical sensor of environmental stimuli, the epithelia of the lungs, gut, and skin are affected by an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents, all of which account for an increase in the prevalence of allergic diseases. A beneficial diverse microbiome is critical in protecting against allergic diseases, and early oral exposure to food allergens are effective at preventing specific food allergies.