Non-NSAID non-Helicobacter pylori ulcer disease, which was believed to account for a minority of bleeding gastroduodenal ulcers, has been increasingly recognized for the past decade. Current data suggest that both relative proportion and actual numbers of patients with non-NSAID non-H. pylori ulcers have increased, whereas the prevalence of H. pylori-positive ulcers has declined. There is evidence to support that non-NSAID non-H. pylori ulcers associate with a higher risk of recurrent ulcer bleeding and a higher overall mortality as compared to H. pylori-positive ulcer disease. Patients with non-NSAID non-H. pylori ulcers are often older, sicker and more frequently experience bleeding episodes while in hospital. The pathogenesis of non-NSAID non-H. pylori ulcer is largely unknown and the efficacy of acid suppressants in the management and prevention of the disease remains to be defined. Well-designed, large-scale studies are awaited to shed light on this emerging condition.