Peptic ulcer disease (PUD) is one of the main lesions responsible for upper gastrointestinal (GI) bleeding, as well as esophageal varices and Mallory–Weiss tear. Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin are the major responsible causes. In cases of upper GI bleeding, urgent endoscopy is performed after stabilization of vital signs. There are several modalities for controlling bleeding in PUD, such as ethanol injection or hypertonic saline with epinephrine. Recurrent bleeding occurs in 20% of patients after endoscopic therapy. The combination of endoscopic intervention and a proton pump inhibitor (PPI) is necessary to achieve hemostasis of active bleeding. It has been reported that high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week) can reduce recurrent bleeding, the need for surgery and mortality from hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole. The metabolism of PPIs is dependent upon P450 2C19 genotypes and the clinical usefulness of genotypic analysis remains to be determined.