The gut is the only organ that can display reflexes and integrative neuronal activity even when isolated from the central nervous system. This activity can be triggered by luminal stimuli that are detected by nerves via epithelial intermediation. Epithelial enterochromaffin cells act as sensory transducers that activate the mucosal processes of both intrinsic and extrinsic primary afferent neurones through their release of 5-hydroxytryptamine (5-HT). Intrinsic primary afferent neurones are present in both the submucosal and myenteric plexuses. Peristaltic and secretory reflexes are initiated by submucosal intrinsic primary afferent neurones, which are stimulated by 5-HT acting at 5-HT1P receptors. 5-HT acting at 5-HT4 receptors enhances the release of transmitters from their terminals and from other terminals in prokinetic reflex pathways. Signalling to the central nervous system is predominantly 5-HT3 mediated, although serotonergic transmission within the enteric nervous system and the activation of myenteric intrinsic primary afferent neurones are also 5-HT3 mediated. The differential distribution of 5-HT receptor subtypes makes it possible to use 5-HT3 antagonists and 5-HT4 agonists to treat intestinal discomfort and motility. 5-HT3 antagonists alleviate the nausea and vomiting associated with cancer chemotherapy and the discomfort from the bowel in irritable bowel syndrome; however, because 5-HT-mediated fast neurotransmission within the enteric nervous system and the stimulation of mucosal processes of myenteric intrinsic primary afferent neurones are 5-HT3 mediated, 5-HT3 antagonists tend to be constipating and should be used only when pre-existing constipation is not a significant component of the problem to be treated. In contrast, 5-HT4 agonists, such as tegaserod, are safe and effective in the treatment of irritable bowel syndrome with constipation and chronic constipation. They do not stimulate nociceptive extrinsic nerves nor initiate peristaltic and secretory reflexes. Instead, they rely on natural stimuli to activate reflexes, which they strengthen by enhancing the release of transmitters in prokinetic pathways. Finally, when all the signalling by 5-HT is over, its action is terminated by uptake into enterocytes or neurones, which is mediated by the serotonin reuptake transporter. In inflammation, serotonergic signalling is specifically diminished in the mucosa. Transcripts encoding tryptophan hydroxylase-1 and serotonin reuptake transporter are both markedly decreased. Successive potentiation of 5-HT and/or desensitization of its receptor could account for the symptoms seen in diarrhoea-predominant and constipation-predominant irritable bowel syndrome, respectively. Symptoms associated with the down-regulation of the serotonin reuptake transporter in the human mucosa in irritable bowel syndrome are similar to the symptoms associated with the knockout of the serotonin reuptake transporter in mice. The observation that molecular defects occur in the human gut in irritable bowel syndrome strengthens the hand of those seeking to legitimize the disease. At least it is not ‘all in your head’. The bowel contributes.