Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased innate immune responses, antigen-presenting cell stimulation, and priming of overt cutaneous disease. In a TH2-promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases.