Peptic ulcer disease is a common condition that manifests its changes on either the gastric or duodenal mucosa and accounts for nearly half of all upper gastrointestinal bleeds admitted to the intensive care unit (ICU). The two major predisposing factors for peptic ulcer disease are infections with Helicobacter pylori and nonsteroidal anti-inflammatory drug (NSAID) use. The lesions caused by these two agents depend not only on the agents but on the characteristics of the gastrointestinal mucosa in the area that they affect. H. pylori is a Gram-negative organism that grows well in the acidic environment of the duodenal bulb. The damage caused by the bacteria in this location leads to further injury and colonization by additional bacteria, which perpetuates the inflammation. In contrast, NSAIDs inhibit cyclo-oxygenase, the enzyme that assists in prostaglandin production. Prostaglandins are an important defense mechanism for the gastric mucosa and inhibition results in a propensity for ulcer formation. Of importance for patients with NSAID-induced ulcer disease, treatment of H. pylori infection, even empirically, might help in achieving a cure and alleviating recurrences. Smoking and stress contribute to the occurrence of both types of peptic ulcer disease and patients should be encouraged to reduce both types of insult.