Exposure of the skin to ultraviolet radiation (UVR) can lead to deleterious effects such as sunburn, photoaging, and the development of skin cancer. UVR has also been shown to reduce local and systemic immune responses in humans and animals. In the recent past it has become clear that neuropeptides mediate some of the effects of UVR-induced immunosuppression. Among the neuropeptides released from cutaneous nerves after exposure to UVR, calcitonin gene-related peptide (CGRP) has been examined most extensively. It appears to lead to a reduction of contact hypersensitivity by inducing mast cells to degranulate and thus release tumor necrosis factor alpha (TNF-alpha) and, most likely, interleukin (IL)-10. Nitric oxide, which is coreleased with CGRP, seems to also play a role in immunosuppression through a yet undiscovered mechanism of action, while substance P may have counterregulatory effects. New evidence suggests that the release of neuropeptides from cutaneous sensory c-fibers after UVR is induced by keratinocyte-derived nerve growth factor. UVR can also induce epidermal and some dermal cells, such as melanocytes, keratinocytes, and dermal microvascular epithelial cells, to produce proopiomelanocortin (POMC) and its derivatives. The POMC product alpha-melanocyte-stimulating hormone (alpha-MSH) has been implicated in suppression of contact hypersensitivity and induction of hapten-specific tolerance, most likely by inducing keratinocytes and monocytes to produce the anti-inflammatory cytokine IL-10. Other POMC derivatives have not yet been investigated with regard to a possible role in UVR-induced effects on immunity.