In the present study VIP-immunoreactive (IR) nerve fibers were found in the skin of several mammalian species (cat, dog, pig and man). They supplied predominantly the arteries and arterial portions of arteriovenous anastomoses. Far fewer VIP-IR nerve fibers innervated veins and arterioles. Capillaries were supplied by VIP-IR fibers only in sweat and Meibomian glands. Some non-vascular VIP-IR nerve fibers were seen in contact with dermal smooth muscle strands. In eccrine sweat glands and in Meibomian glands VIP-IR fibers were targeting glandular cells. In addition, VIP-IR nerve fibers innervated the upper parts of facial hair follicles. In non-neuronal localization VIP-IR occurred in Merkel cells in all species and sites, while the intraepidermal axons consistently were not VIP-IR. Radioimmunoassay of different skin regions of cats also suggested both a neuronal and a Merkel cell origin of VIP-IR. Under physiological conditions VIP which is released from its neuronal and non-neuronal cutaneous pools may have an impact on thermoregulation by influencing blood flow and sweat production. It may also modulate axon-endings in Merkel cell-axon complexes and hair follicle receptors. Under pathological conditions an enhanced release of cutaneous VIP may lead to local inflammatory processes partly mediated via release of histamine from cutaneous mast cells.