The etiology of esophageal mucosal injury is complex, since it may involve the reflux of gastric acid, bile acid, and pancreatic juice, external factors such as drugs and alcohol, or functional factors such as esophagogastric motility. The mechanism of esophageal mucosal injury has gradually been understood at the molecular biological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines (interleukin-6 and -8), leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). In addition, nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with anti-inflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.