The serotonergic neurotransmission is known as a neuromodulatory system exerting its activity in the central nervous system (CNS) as well as at the periphery. The anatomical and morphological organization of the system based on a marked centralization of the cellular bodies and the large, almost ubiquitary, presence of axonal projections of the neurons is in good agreement with this modulatory role. Furthermore, a very high number of varicosities located along the axonal branches are capable of releasing serotonin (5-HT). The amine stimulates a number of different specific receptor types which allows 5-HT to exert different activities on its various cellular targets. Among these receptors, the 5-HT1B subtypes play a particular role as they are autoreceptors located on 5-HT neurons terminals and heteroreceptors located on non-serotonergic terminals where they control the release of the neurotransmitter. 5-HT-moduline, an endogenous tetrapeptide, regulates the efficacy of these 5-HT1B receptors, hence, is able to control the serotonergic activity in a synchronous manner for the various varicosities from a single neuron and thus may favour the differential effect of that neuron on distinct cerebral functions. Accordingly, the peptide allows the 'fine tuning' of the cerebral activity by the serotonergic system to elaborate the response given by the brain to a particular stimulus, that is, stress situations. At the periphery, the serotonergic system also appears to possess a regulatory activity via 5-HT1B receptors. In particular, the receptors located on immunocompetent cells control their activity and are themselves regulated by 5-HT-moduline likely originating from adrenal medulla and released after acute stress. The serotonergic system appears to play a major role in the reciprocal signalling existing between the neuronal and the immune system. The participation of 5-HT-moduline is likely in physiological functions as well as in pathological disorders affecting central and peripheral activities.