The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.