Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.