Neuropeptides present in the peripheral nervous system (PNS) and central nervous system (CNS) modify diverse functions of human, murine and guinea pig mononuclear leukocytes in vitro and in vivo by receptor-mediated mechanisms. Both stimulatory and inhibitory effects on lymphocytes and macrophages have been demonstrated for different neuropeptides in vitro at concentrations which are similar to those in the circulation and in tissues. The dissociation constant (KD) for the binding of a neuropeptide to its lymphocyte receptor is within the range of concentrations that evoke lymphocyte responses critical to immunity and hypersensitivity. The receptor-mediated interactions of diverse neuropeptides with immunocompetent cells provide one mechanism through which the PNS may influence localized immune responses and the CNS may alter systemic immunity.