Intestinal motility, secretion, and blood flow are controlled and integrated by the enteric nervous system (ENS). The ENS is like a "brain-in-the-gut," with many of the neurophysiologic properties of the central nervous system. Serotonin is a neurotransmitter at synapses in the microcircuits of the ENS. Serotonin is also released from enterochromaffin cells and inflammatory/immune cells to act at serotonergic receptors on neurons of the ENS. Four important actions are (1) fast and (2) slow excitation of enteric neurons, (3) presynaptic inhibition of neurotransmitter release at synapses in ENS microcircuits, and (4) excitation of intestinal sensory afferent fibers. Fast excitation and stimulation of sensory afferents are mediated by 5-HT(3) serotonergic receptors and slow excitation by 5-HT(1P) receptors. Presynaptic inhibitory receptors are not conclusively defined. The efficacy of a new 5-HT(3) receptor blocking drug in the treatment of the diarrhea-predominant form of the irritable bowel syndrome in women suggests the importance of this receptor subtype in the mediation of neurogenic secretory diarrhea, motility abnormality, and abdominal pain and discomfort.