This narrative review covers the mechanisms of actions of trendy drugs approved for or proposed for calming the irritable bowel. Many drugs that target functional gastrointestinal disorders (FGIDS), which includes IBS, have their actions in the enteric nervous system (i.e., the brain-in-the-gut). The in-depth insight into fundamental neurophysiology, which is essential for understanding how the drugs act to achieve their effects, is covered from a neurogastroenterological view point. Pharmacotherapeutic research in FGIDS, which is now lagging, is focused mainly on symptom control. Major progress will require a change to orientation on the malfunction underlying each of the symptoms that constitute Manning, Rome I and Rome II symptom-based criteria for FIGD diagnoses. A high incidence of autoimmune degenerative neuropathy in the enteric nervous system occurs in IBS and is postulated to be the cause of symptoms emerging from failure of normal neural control of motility, blood flow and secretory glands, in concert with sensitization of spinal and vagal sensory mechanisms.