The skin has recently been found to be an extra-adrenal site for glucocorticoid (GC) synthesis that likely acts to modulate local inflammation. Psychological, physiological, and physical stress, both acute and chronic, triggers immune-protective or -damaging responses, including increases in systemic GC levels, which, according to Lin et al. (this issue), may be beneficial in inflammatory skin disease. However, little is known about the interplay between local and systemic production of GCs and the effect of stress (local or systemic) in regulating tissue-specific GC synthesis, its impact on skin homeostasis, and its effect of skin disease.