There is increasing evidence that the cutaneous nervous system modulates physiological and pathophysiological effects including cell growth and differentiation, immunity and inflammation as well as tissue repair. Both cutaneous nervous fibers and inflammatory cells are able to release neuromediators and thereby activate specific receptors on target cells in the skin or transient immunocompetent cells. Cutaneous neuromediators include classical neurotransmitters such as catecholamines and acetylcholine being released from the automatic nervous system or cutaneous cells. On the other hand neuropeptides including substance P, calcitonin gene related peptide (CRGP), vasointestinal peptide (VIP) or proopiomelanocortin (POMC) derived peptides such as alpha melanocyte stimulating hormone (alphaMSH) may be released from sensory or autonomic nerve fibers and several epidermal as well as dermal cells. Neuropeptides are known to activate a variety of cutaneous cells through high affinity neuropeptide receptors or by direct activation of intracellular G-protein signalling cascades. Via the modulation of transcription factor activation (NF-kappaB, AP-1, STAT-3) they regulate the expression of adhesion molecules and proinflammatory cytokines in different cells and thereby function as modulators of immune and inflammatory reactions. Accordingly, neuropeptides such as CGRP or alphaMSH in vitro were found to downregulate costimulatory molecule expression on dendritic cells and in vivo via the generation of suppressor T-lymphocytes to induce hapten specific tolerance. Proteinases such as tryptase or neural endopeptidase inactivate neuropeptides in the extracellular space or at the cell surface thereby terminating neuropeptide induced inflammatory or immune responses. Proteinase-activated receptors (PAR) are recently described receptors that may have high impact in regulating cutaneous neurogenic inflammation. In the skin PAR-2 being expressed on sensory neurons and endothelial cells is self activated by tethered peptide ligands that are exposed after extracellular amino-terminal cleavage by trypsin or mast cell tryptase. PAR-2 agonists were found to induce the release of CGRP and SP which mediate vasodilation, plasma extravasation as well as the expression of adhesion molecules on vascular endothelial cells and thus elicit neurogenic inflammation. These findings indicate that the neuromediator network including neuropeptide receptors as well as proteinases play an important role in the maintenance of tissue integrity and the regulation of inflammatory and immune responses in the skin.