The response to systemic stress is organized along the hypothalamic-pituitary adrenal axis (HPA), whereas the response to a peripheral stress (solar radiation) is mediated by epidermal melanocytes (cells of neural crest origin) responsible for the pigmentary reaction. Melanocytes express proopiomelanocortin (POMC), corticotropin releasing hormone (CRH), CRH receptor-1 (CRH-R1) and can produce corticosterone. In the present study, incubation of normal epidermal melanocytes with CRH was found to trigger a functional cascade structured hierarchically and arranged along the same algorithm as in the hypothalamic-pituitary-adrenal (HPA) axis: CRH activation of CRH-R1 stimulated cAMP accumulation, increased POMC gene expression and production of ACTH. CRH and ACTH also enhanced production of cortisol and corticosterone, while cortisol production was also stimulated by progesterone. The chemical identity of the cortisol was confirmed by liquid chromatography-mass spectrometry² (LC/MS²) analyses. POMC gene silencing abolished the stimulatory effect of CRH on corticosteroid synthesis indicating that this is indirect, and mediated via production of ACTH. Thus, the melanocyte response to CRH is highly organized along the same functional hierarchy as the HPA axis. This pattern demonstrates the conserved nature of the response to stress with similar activation sequence at the single cell and whole body levels.