Many cutaneous disorders are adversely affected by psychological stress (PS), but the responsible mechanisms are poorly understood. Recent studies have demonstrated that PS decreases epidermal proliferation and differentiation, impairs permeability barrier homeostasis, and decreases stratum corneum integrity. PS also increases the production of endogenous glucocorticoids (GC), and both systemic and topical GC cause adverse effects on epidermal structure and function similar to those observed with PS. We therefore hypothesized that increased endogenous GC in PS mediates its adverse cutaneous effects. To test this hypothesis, we used two independent approaches, administering either RU-486, a GC receptor antagonist that inhibits GC action, or antalarmin, a corticotropin-releasing hormone (CRH) receptor antagonist that prevents increased GC production in the face of PS. Inhibition of either GC action or production prevents the PS-induced decline in epidermal cell proliferation and differentiation, impairment in permeability barrier homeostasis, and decrease in stratum corneum (SC) integrity. Moreover, the pathophysiological basis for the abnormality in permeability barrier homeostasis; i.e., decreased lamellar body production and secretion, is restored toward normal by inhibition of GC action. Similarly, the mechanistic basis for the decrease in SC integrity, i.e., a reduction in corneodesmosomes, is also normalized by inhibition of GC action. Thus many of the adverse effects of PS on epidermal structure and function can be attributed to increased endogenous GC and conversely, approaches that either reduce GC production or action might benefit cutaneous disorders that are provoked or exacerbated by PS.