Information about the conditions of all tissues in the body is conveyed to the central nervous system through afferent neurons. Uniquely amongst peripheral organs, the intestine has numerous additional afferent neurons, intrinsic primary afferent neurons that have their cell bodies and processes in the enteric plexuses and do not project to the central nervous system. They detect conditions within the gut and convey that information to intrinsic reflex pathways that are also entirely contained inside the gut wall. Intrinsic primary afferent neurons respond both to the presence of material in the gut lumen and to distension of the gut wall and initiate reflex changes in contractile activity, fluid transport across the mucosa and local blood flow. They also function as nociceptors that initiate tissue-protective propulsive and secretory reflexes to rid the gut of pathogens. The regulation of excitability of intrinsic primary afferent neurons is through multiple ion channels and ion channel regulators, and their excitability is critical to setting the strength of enteric reflexes. The intestine also provides afferent signals to sympathetic pre-vertebral ganglia. The signals are conveyed from the gut by intestinofugal neurons that have their cell bodies within enteric ganglia and form synapses in the sympathetic ganglia. Intestinofugal neurons form parts of the afferent limbs of entero-enteric inhibitory reflexes. Because the unusual afferent neurons of the small intestine and colon make their synaptic connections outside the central nervous system, the neurons and the reflex centres that they affect are potential targets for non-central penetrant therapeutic compounds.