SUMMARYPrevious work has indicated that the dermis and epidermis of skin contains abundant nerve ®bres closely associated with Langerhans' cells. We have investigated whether these nerve endings are necessary for inducing and evoking a contact sensitivity (CS) response. Topical application of a general or a peptide (calcitonin gene-related peptide and substance P)-speci®c neurotoxin was employed to destroy the nerve ®bres at skin sites subsequently used to induce or evoke the CS response. Elimination of nerve ®bres abolished both induction and effector stages of the speci®c CS response. Denervation did not destroy the local Langerhans' cells, which were observed in increased numbers, or prevent them from migrating to lymph nodes. The local CS response was also abolished by systemic deletion of capsaicin-sensitive nerve ®bres, suggesting that the loss of response was not non-speci®c but associated with the loss of speci®c nerve ®bres. The results indicate that peptidergic nerve ®bres are required to elicit a CS response and may be vital to the normal function of the immune system.