When the barrier to acid back-diffusion is disrupted, there is a protective increase in gastric mucosal blood flow to help remove the back-diffusing acid. Only recently has the mechanism for calling forth this protective hyperemia been determined. The gastric mucosa and submucosa are innervated by many capsaicin-sensitive sensory nerve fibers containing vasodilator peptides. The gastric mucosal sensory neurons monitor for acid back-diffusion, and, when this process occurs, signal for a protective increase in blood flow via release of calcitonin gene-related peptide from the submucosal periarteriolar fibers. The endothelium-derived vasodilator, nitric oxide, plays an important role both in the maintenance of basal gastric mucosal blood flow and in the increase in blood flow that accompanies pentagastrin-stimulated gastric acid secretion. It also interacts with the capsaicin-sensitive sensory nerves in the modulation of the microcirculation to maintain mucosal integrity. Finally, it has been shown that neutrophils play an important role in various forms of mucosal injury. The leukocytes adhere to the vascular endothelium and contribute to injury by reducing blood flow via occlusion of microvessels, as well as by releasing mediators of tissue damage.