The maintenance of gastrointestinal (GI) mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. Two populations of extrinsic primary afferent neurons, vagal and spinal, subserve this goal through different mechanisms. These sensory neurons react to GI insults by triggering protective autonomic reflexes including the so-called cholinergic anti-inflammatory reflex. Spinal afferents, in addition, can initiate protective tissue reactions at the site of assault through release of calcitonin gene-related peptide (CGRP) from their peripheral endings. The protective responses triggered by sensory neurons comprise alterations in GI blood flow, secretion, and motility as well as modifications of immune function. This article focuses on significant advances that during the past couple of years have been made in identifying molecular nocisensors on afferent neurons and in dissecting the signaling mechanisms whereby afferent neurons govern inflammatory processes in the gut.