The skin as a barrier and immune organ is exposed to omnipresent environmental challenges such as irradiation or chemical and biologic hazards. Neuropeptides released from cutaneous nerves or skin and immune cells in response to noxious stimuli are mandatory for a fine-tuned regulation of cutaneous immune responses and tissue maintenance and repair. They initialize host immune responses, but are equally important for counter regulation of proinflammatory events. Interaction of the nervous and immune systems occurs both locally – at the level of neurogenic inflammation and immunocyte activation – and centrally – by controlling inflammatory pathways such as mononuclear activation or lymphocyte cytokine secretion. Consequently, a deregulated neurogenic immune control results in disease manifestation and frequently accompanies chronic development of cutaneous disorders. The current understanding, therapeutic options, and open questions of the role that neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide, neuropeptide Y, or others play in these events are discussed. Progress in this field will likely result in novel therapies for the management of diseases characterized by deregulated inflammation, tissue remodeling, angiogenesis, and neoplasm.Abbreviations: AM, adrenomedullin; APC, antigen presenting cells; BK, bradykinin; B1 and B2, BK receptors; CGRP, calcitonin gene-related peptide; DC, dendritic cell; IP, inositol 1,4,5-phosphate; NEP, neutral endopeptidase; NGF, nerve growth factor; PACAP, pituitary adenylate cyclase activating polypeptide; SP, substance P; TRPV, transient receptor potential channel vanilloid subfamily; VPAC1 and VPAC2, receptors for VIP/PACAP; VIP, vasoactive intestinal peptide