I coined the now universally accepted term, brain-in-the-gut, for the enteric nervous system in a review published in the 1981 issue of the Annual Review of Physiology . This was in view of discoveries in my laboratory and others that the main physiological processes in the digestive tract are controlled by an independent integrative nervous system with neural circuitry containing about 100 million neurons, all within the walls of the gut. Neuronal electrical behavior and synaptic neurotransmission in the microcircuits of the second brain are essentially the same as in the “big brain”. The microcircuits in the second brain contain a library of neural programs (think I-phone, I-pad apps) that determine behavior in specialized states including postprandial, interdigestive, emesis and defense against threatening invasions from the outside. My mantra to medical students over 45 years continues to be; “understanding how a system works normally is prerequisite for determination of what is wrong, making a diagnosis and formulating a rational therapeutic plan”. My talk will explain how the brain-in-the-gut is involved in the pathophysiology of several disorders, such as the irritable bowel syndrome, Hirschsprung Disease, food allergies, enteric infections, constipation, diarrhea, psychogenic stress and opioid drug effects.