The skin offers an ideally suited, clinically relevant model for studying the crossroads between peripheral and systemic responses to stress. A 'brain-skin connection' with local neuroimmunoendocrine circuitry underlies the pathogenesis of allergic and inflammatory skin diseases, triggered or aggravated by stress. In stressed mice, corticotropin-releasing hormone, nerve growth factor, neurotensin, substance P and mast cells are recruited hierarchically to induce neurogenic skin inflammation, which inhibits hair growth. The hair follicle is both a target and a source for immunomodulatory stress mediators, and has an equivalent of the hypothalamus-pituitary-adrenal axis. Thus, the skin and its appendages enable the study of complex neuroimmunoendocrine responses that peripheral tissues launch upon stress exposure, as a basis for identifying new targets for therapeutic stress intervention.