The integrity, high functional activity and sufficient regeneration rate of gastric mucosa (GM) in harsh conditions is very challenging pathophysiological demand. The health of gastric epithelium highly depends of efficiency of redox balance maintenance, antioxidant defense and activity of detoxifying systems within the cells as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in (patho)physiological adaptive reactions, cells signaling, and are also implicated in pathogenesis of numerous gastric diseases. However, while mechanisms and consequences of HNE and its protein adducts production in response to strong stressors during acute and chronic gastric injury are well studied, many other important issues related to gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, the relevance of antioxidants for HNE-related redox homeostasis in GM and many other still need extensive studies and new comprehensive approaches. Therefore, in order to address existing issues preclinical studies and clinical intervention trials are required, which should include also determination of HNE preferably by immunohistological and specific HNE-His ELISA analyses.