The skin is a unique immunologic organ that acts as an interface between the external environment and the systemic immune response. As such, it may react directly with allergens that are applied epicutaneously, thereby influencing the systemic allergic response. It is well known that atopic dermatitis (frequently in association with food allergy) predates the development of asthma and allergic rhinitis by several years. The possibility that atopic dermatitis may influence the course of asthma is suggested by several interesting observations. First, children with atopic dermatitis and positive skin tests to allergens frequently have more severe asthma than asthmatic children without atopic dermatitis. Second, because total serum IgE is strongly associated with the prevalence of asthma, it raises the interesting question of whether allergen sensitization through the skin predisposes to more severe and persistent respiratory disease because of its effects on the systemic allergic response. Indeed, epicutaneous sensitization of mice to a protein antigen induces both a localized allergic dermatitis and hyperresponsiveness to methacholine, which suggests that epicutaneous exposure to antigen in atopic dermatitis may enhance the development of asthma. Finally, systemic immune activation in atopic dermatitis is supported by the observation that these patients have increased numbers of circulating activated T(H)2 cells, eosinophils, macrophages, and IgE. Many of the markers of leukocyte activation have been shown to correlate with the severity of atopic dermatitis disease. This systemic activation might facilitate local infiltration of primed T cells, eosinophils, and macrophages into the respiratory mucosa after inhalation of allergen in genetically predisposed hosts. The systemic aspects of atopic dermatitis, with an emphasis on respiratory effects, are summarized.