We have highlighted the recent findings relating to gastroduodenal mucosal defense, including elements that may contribute to the failure of defense systems and factors that enhance mucosal healing, focusing on findings that elucidate new pathophysiological mechanisms.Bicarbonate secretion is mediated by multiple types of prostaglandin E synthases, including membrane-bound prostaglandin E synthase-1. Mucins, growth factors, and trefoil factors are involved in accelerating gastric injury healing through epithelial reconstruction. A combination of NSAIDs and bile induce greater damage on the mucosa than if the two agents were acting alone. Proton pump inhibitors defend the mucosa from injury by promoting cellular restitution as well as inhibiting gastric acid secretion and reactive oxygen species (ROS) damage. Roxatidine, a novel H2 receptor antagonist, acts through a mechanism that involves nitric oxide. Melatonin enhances angiogenesis through the upregulation of plasma levels of gastrin and matrix metalloproteinase expression. The mucosal protective drug polaprezinc exhibits ROS-quenching activities. Lipopolysaccharides induce oxidative stress mediated by p38 mitogen-activated protein kinase (p38 MAPK). Aging weakens gastroduodenal mucosal defense mechanisms.There is a wide array of pathways leading to gastroduodenal mucosal injury in addition to protective defense mechanisms that counteract them to maintain homeostasis. Increased understanding of these systems may help identify novel molecular targets for the prevention and treatment of mucosal injury.