The role of structural components and cell adhesion molecules in the epidermis has not been fully studied in terms of the pathophysiology of atopic dermatitis (AD). In this issue, Omori-Miyake et al. (2014) report that IL-4 and IL-13, which are Th2 cytokines, downregulate the expression of keratins and desmosomal cadherins in a STAT6-dependent manner, leading to keratinocyte fragility in the face of mechanical stress. Th2 cytokine-induced instability of the epidermis may be considered to be one of the pathogenic mechanisms that have roles in AD.