The basic mechanisms underlying cytoprotection of gastrointestinal mucosae against damage are not understood. One hypothesis is that the initial and primary system affected by a cytoprotective agent is the local circulation of the tissue that is being protected. According to this circulatory hypothesis, a cytoprotective prostaglandin would increase gastric mucosal blood flow, thereby ameliorating the effect of topical damaging agents, such as ethanol, aspirin or bile salts. Four questions need to be considered in order to evaluate the circulatory hypothesis: (i) What degree of ischemia is necessary to break the gastric mucosal barrier? (ii) Is peptic ulcer disease due to local ischemia of the mucosa? (iii) Do mucosal damaging agents invariably reduce gastric blood flow? (iv) Do cytoprotective agents invariably increase gastric blood flow? A survey of available literature concerning blood flow and damage to the gastric mucosa suggests that: (i) severe degrees of gastric ischemia are necessary to impair vital functions of the epithelial cells of the stomach; (ii) peptic ulcer disease is not a manifestation of isolated gastric ischemia; (iii) mucosal damaging agents do not invariably reduce gastric blood flow; and (iv) cytoprotective drugs do not invariably increase gastric mucosal blood flow. The weight of available evidence does not support the circulatory hypothesis about the mechanism of cytoprotection.