Vagal and spinal afferents represent the information superhighways that convey sensory information from the gut to the central nervous system. These afferents are sensitive to both mechanical and chemical stimuli. Vagal afferents terminate in the muscle layers and in the mucosa. Muscle afferents are activated at physiological levels of distension and during peristalsis. In contrast, spinal afferents encode supraphysiological levels of intestinal pressure. Vagal and spinal afferents also express a wide range of membrane receptors to a variety of chemical mediators generated from both within and outside the gut wall. Some of these receptors are part of a modality specific transduction pathway involved in sensory signalling from the gut lumen to vagal afferent endings in the mucosa. Others, which are activated by substances derived from multiple cellular sources during ischaemia, injury, or inflammation act in a synergistic way to cause acute or chronic sensitisation of the afferent nerves to mechanical and chemical stimuli. Understanding the mechanisms that underlie hypersensitivity may have implications for the pharmaceutical approach to the treatment of functional bowel disorders like irritable bowel syndrome.