Administration of acid-inhibiting drugs in the prevention of stress ulcer bleeding is based on the hypothesis that pepsin activity is pH-dependent. In the treatment of peptic ulcer bleeding, acid-inhibition is based on the hypothesis that clot formation and clot lysis depend on intraluminal pH. Medications used in the prophylaxis of stress ulcer bleeding comprise antacids, sucralfate, H2-receptor antagonists and proton pump inhibitors (PPIs). Two studies show that prophylaxis with ranitidine is more effective than prophylaxis with sucralfate. PPIs give a more predictable and sustained pH control during prolonged dosing than ranitidine. Two trials show that patients who receive omeprazole run a significantly lower risk of bleeding than patients receiving ranitidine. The optimal initial treatment for bleeding peptic ulcers in patients with active bleeding or non-bleeding visible vessel is endoscopic therapy. Among patients with non-bleeding visible vessels or adherent clots who do not undergo endoscopic therapy, acid-inhibition with PPIs may significantly reduce rebleeding rate and need for surgery. After endoscopic therapy acid-inhibition with PPIs may have a beneficial effect on hemostasis. One direct comparative trial showed no significant difference in clinical outcomes between patients whether treated with high-dose or low-dose PPI. The use of multiple medications to treat concurrent conditions in ICU patients or bleeding peptic ulcer patients increases the risks of clinically important metabolic drug interactions. More recently developed PPIs are less dependent on CYP2C19 and probably have a lower potential for metabolic drug interactions. For both indications the optimal dose PPI has to be established.