There is evidence that foetal body movements first occur at 6 weeks gestation, and that the reflex arc is functional at 8 weeks. This correlates with the detection of the sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) in spinal cord at 10 weeks gestation. However, the development of cutaneous neuropeptide-containing nerves is not well documented in humans. We have investigated the early appearance and distribution pattern of CGRP, SP, vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), as well as those of the general neuronal marker protein gene product 9.5 (PGP) in various areas of foetal skin at different gestational ages. PGP-immunoreactive nerves were first seen in the subepider-ma1 plexus at 6 weeks gestational age. Initially, the immunoreactive nerves are thick, club-shaped and distributed in the superficial dermis. Beaded adult-like fibres become more numerous only at later ages (10-12 weeks), and extend from this plexus to penetrate the epidermis. Histologically, the skin of the hand develops faster than that of other body areas and at 9 weeks, more PGP-immunoreactive nerves were seen in the palm than in the dorsum. Primitive sweat glands were first noted in axillary skin at 1 7 weeks, accompanied by a few PGP-immunoreactive nerves. Occasional, small CGRP-immunoreactive fibres were first noticed in the dermis at 7 weeks, but it was a t 1 7 weeks that the presence of this neuropeptide was unequivocal in the subepidermal plexus. Sparse VIP-, SP-and NPY-immunoreactive fibres were not found until 16-17 weeks gestation, when they were seen in the dermis and around small blood vessels. These results show that development of nerves containing sensory neuropeptides precedes that of autonomic fibres, and that the former are present in developing cutaneous innervation after neuronal protein markers are detectable. The timing of the appearance of CGRP immunoreactivity in the skm correlates with that of the peptide in spinal cord, which is consistent with the reported reflex movements of the foetus. The morphological and functional development of cutaneous neuronal elements shows a close correlation that might provide some insight into the process of nerve regeneration in adult skin.