Duodenal ulcer disease is a chronic condition with multiple causes. These causes have in common the ability to increase acid delivery to the duodenum, the ability to decrease duodenal defense against an acid load, or a combination of these abilities. Some causes of duodenal ulcer disease are acquired; others are genetically determined. Ulcer recurrence in smokers is common because nicotine impairs the capacity of the duodenum to buffer an acid load. Duodenal ulcer recurrences are also common in nonsmokers because treatments fail to correct underlying pathogenetic mechanisms of ulcer disease. Optimum therapy should take into account the role of offensive and defensive factors in the development of the disease.