Calcitonin gene‐related peptide (CGRP) has been viewed as a neuropeptide and vasodilator. However, CGRP is more appropriately thought of as a pleiotropic signalling molecule. Indeed, CGRP has key regulatory functions on immune and inflammatory processes within the skin. CGRP‐containing nerves are intimately associated with epidermal Langerhans cells (LCs), and CGRP has profound regulatory effects on Langerhans cell antigen‐presenting capability. When LCs are exposed to CGRP in vitro, their ability to present antigen for in vivo priming of naïve mice or elicitation of delayed‐type hypersensitivity is inhibited in at least some situations. Administration of CGRP intradermally inhibits acquisition of immunity to Th1‐dominant haptens applied to the injected site while augmenting immunity to Th2‐dominant haptens, although the cellular targets of activity in these experiments remain unclear. Although CGRP can be a pro‐inflammatory agent, several studies have demonstrated that administration of CGRP can inhibit the elicitation of inflammation by inflammatory stimuli in vivo. In this regard, CGRP inhibits the release of certain chemokines by stimulated endothelial cells. This is likely to be physiologically relevant as cutaneous blood vessels are innervated by sensory nerves. Exciting new studies suggest a significant role for CGRP in the pathogenesis of psoriasis and, most strikingly, that CGRP inhibits the ability of LCs to transmit the human immunodeficiency virus 1 to T lymphocytes. A more complete understanding of the role of CGRP in the skin immune system may lead to new and novel approaches for the therapy of immune‐mediated skin disorders.