The association between colonization of the stomach by Helicobacter pylori and peptic ulcer disease has stimulated a renewal of interest in the factors that render the gastric mucosa resistant to injury induced by endogenous secretions and ingested toxins. Mucosal defense consists of a complex network of components that function in concert with one another. This network includes: 1) the extramucosal components such as acid, mucus, surface-active phospholipids, and bicarbonate; 2) the epithelium itself; 3) the microcirculation and sensory afferent neurons beneath the epithelium; 4) the mucosal immune system; and 5) the ability of the mucosa to undergo repair. In the past two decades, an enormous amount has been learned about the cellular and molecular basis of the various components of mucosal defense, including a better understanding of the chemical substances that coordinate mucosal responses to injury. In this paper, we review the factors that contribute to mucosal defense, the cellular and molecular mechanisms through which mucosal defense is modulated, and the chemical mediators that play key roles in this process.