The skin, as the largest organ of the body, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stressors such as bursts of radiation (solar, thermal), mechanical energy, or chemical and biological insults. Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for dealing with the stressors. Activities of the skin are mostly regulated by local cutaneous factors and stressed skin can generate signals to produce rapid (neural) or slow (humoral) responses to local or systemic levels. Thus, the skin neuroendocrine system is comprised of locally produced neuroendocrine mediators that interact with corresponding specific receptors through para- or autocrine mechanisms. Furthermore, it is known for several years that the corticotropin-releasing hormone (CRH)/ pro-opiomelanocorticotropin (POMC) skin system fulfils analogous functions to the hypothalamic-pituitary-adrenal (HPA) stress axis. Additionally, skin cells produce hormones, neurotansmitters and neuropeptides, having the corresponding receptors and the skin itself is able to fulfill a multidirectional communication between endocrine, immune and central nervous systems as well as other internal organs. In summary, the skin expresses an equivalent of the prominent hypothalamic-pituitary-adrenal stress axis that may act as a cutaneous defense system, operating as a coordinator and executor of local responses to stress, in addition to its normal function: the preservation of body homeostasis.