The mechanisms by which the gastroduodenal mucosa maintains viability and normal functioning despite its intensely caustic environment have puzzled clinicians and investigators alike for at least 150 years. Protective mechanisms have been divided into three main categories: preepithelial (mucus and bicarbonate secretion), epithelial (cellular buffering, mucosal architecture and permeability), and postepithelial mechanisms (mucosal blood flow). Within each category are many other factors that bear on the ability of the mucosa to withstand constant changes of luminal pH. We will summarize some of the recent findings that pertain to the nature and regulation of these defense mechanisms in the context of a historical overview. Therapeutic implications of these findings will also be presented in the discussion of novel antiinflammatory compounds designed to upregulate simultaneously several defensive mechanisms, with the expectation that gastroduodenal damage will be minimized.