The pathogenesis of peptic ulcer disease is multifactorial, including the effects of Helicobacter pylori, gastric acid, pepsin, gastroduodenal motility, smoking and nicotine, and the complex interaction of an array of other so-called aggressive and protective factors. Since the discovery and acceptance of H. pylori as a major etiologic agent in peptic ulcer disease, the role of smoking has received less attention. Smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and ulcer relapse is more likely in smokers. These clinical observations may be explained by the adverse effects that smoking has on mucosal aggressive and protective factors. Of the aggressive factors, smoking appears to have no consistent effect on acid secretion. However, smoking impairs the therapeutic effects of histamine-2 antagonists, may stimulate pepsin secretion, promotes reflux of duodenal contents into the stomach, increases the risk for and harmful effects of H. pylori, and increases production of free radicals, vasopressin, secretion by the pituitary, secretion of endothelin by the gastric mucosa, and production of platelet activating factor. Smoking also affects the mucosal protective mechanisms. It decreases gastric mucosal blood flow and inhibits gastric mucous secretion, gastric prostaglandin generation, salivary epidermal growth factor secretion, duodenal mucosal bicarbonate secretion, and pancreatic bicarbonate secretion. These adverse effects of smoking on aggressive and protective factors quality it as an important contributor to the pathogenesis of peptic ulcer disease and indicate that smoking plays a significant facilitative role in the development and maintenance of peptic ulcer disease.