Alone among organs of the body, the gut is able to mediate reflexes in the absence of input from the brain or spinal cord. This ability appears to be caused by the secretion of serotonin (5-HT) by enterochromaffin (EC) cells of the mucosal epithelium. This 5-HT is secreted into the wall of the gut, where it stimulates the mucosal processes of intrinsic and extrinsic primary afferent neurons. The intrinsic primary afferents, which are activated by 5-HT1P/4 receptors, initiate peristaltic and secretory reflexes. The extrinsic primary afferent neurons send distress and other signals to the central nervous system. Extrinsic nerves are activated by 5-HT(3) receptors. The 5-HT that is involved in mucosal signaling is inactivated by uptake into mucosal epithelial cells, which are mediated by an integral membrane protein called the serotonin reuptake transporter (SERT). The epithelial SERT is the same molecule as that which transports 5-HT in the central and enteric nervous systems. Increasing evidence suggests that abnormal enteric release or inactivation of 5-HT is involved in the pathogenesis of irritable bowel syndrome (IBS). Spread of 5-HT to inappropriate sites in IBS may activate 5-HT(3) receptors on extrinsic afferent fibers and motor neurons, giving rise to visceral hypersensitivity and abnormal motility, respectively. A potent 5-HT(3) antagonist, such as alosetron, can prevent both of these effects and is therefore useful in treating IBS. 5-HT also appears to function as a growth factor in the development of enteric neurons. The developmental effects of 5-HT are mediated by the 5-HT(2B) receptor, which is developmentally regulated. The importance of serotonergic mechanisms in enteric physiology probably accounts for the gastrointestinal "side effects" of compounds that inhibit SERT. The newly discovered role of 5-HT in enteric neuronal development suggests that drugs that interfere with the action or inactivation of 5-HT should be used in pregnancy only with extreme caution, if at all.