This review provides evidence that gastroduodenal mucosal injury is a complex process because of the heterogenous structure and multiple functions of the gut. The action of exogenous etiologic agents is usually mediated in part of amplified by endogenous mediators that very often exert biphasic, i.e., damaging and protective, effects. The pathogenetic pathways involved are direct/indirect chemical injury, vascular damage and its consequences, and acute or chronic inflammatory processes following infectious, chemical, or ischemic injury. The role of oxygen, free radicals, calcium, and proteases as well as the components and forms of gastroduodenal injury, e.g., reversible and irreversible cell injury, tissue necrosis, and acute and chronic inflammation, are also briefly discussed.