Research performed in the laboratory and the clinic over the past several years has added to our understanding of the mechanisms that are operative in protecting the epithelial lining of the stomach and duodenum from injury and ulceration, most frequently caused by necrotic agents in the lumen. The defensive mechanism of the gastroduodenal mucosa comprises a series of physical, chemical, biologic, and immunologic barriers or mechanisms that act in concert to either prevent or limit cellular injury or transformation. The field of gastroduodenal defense can be subdivided into the following four areas: extracellular mucus barrier properties; membrane and ion transport properties; cellular factors promoting growth and restitution; and vascular, neural, and inflammatory factors ensuring optimal tissue perfusion and immune responsiveness, respectively. In addition, a great deal can be learned about gastroduodenal defense by studying the effects of ulcerogenic factors and conditions on the defensive mechanisms described here and specifically how they may be compromised by nonsteroidal anti-inflammatory drugs and Helicobacter pylori infection. This review presents interesting and noteworthy findings impacting on these properties contributing to gastroduodenal defense since the prior review article on this subject appearing in this journal.