Studies show that the gastroduodenal mucosal barrier is damaged by pepsin under conditions in which it is resistant to acid alone. The continuous layer of adherent mucus gel provides a diffusion barrier to luminal pepsin, preventing its access to the underlying epithelium. Pepsin has mucolytic activity and will progressively digest the adherent mucus layer at its luminal surface, although normally this is balanced by secretion of new mucus to maintain a continuous barrier. In peptic ulcer disease the proportion of peptic activity in gastric juice attributable to pepsin type 1 is significantly raised (four to five-fold). Pepsin 1 has increased mucolytic activity compared with the major component, pepsin 3, both at the optimal pH of 2 (twofold increase in activity) and at higher pH values up to pH 5 (sixfold increase in activity at pH 4). Structural studies show that the gel forming polymeric mucin of the antral adherent mucus barrier is deficient in peptic ulcer disease. This breakdown of the mucus barrier in peptic ulcer patients can be attributed to the increased pepsin activity of gastric juice seen in this disease, although other explanations are also possible. The increased pepsin activity of gastric juice in peptic ulcer patients is compatible with the concept 'no acid, no pepsin, no ulcer'.