Functional oesophageal epithelial defense, including cell proliferation, restitution, buffers and ion transporters, plays a significant role in maintaining mucosal integrity and enabling rapid repair after injury. Growth factors such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are associated with oesophageal epithelial proliferation or restitution. Na+/H+ exchanger-1, an ion transporter, regulates intracellular pH and cell volume, and may have roles in cell proliferation, migration and survival. Cytokine, adhesion molecules, cyclooxygenase-2 and free radicals are associated with oesophageal inflammation and breach of the functional epithelial defense. Although the oesophagus does not have strong functional epithelial defense against acid, this defensive mechanisms may be involved in the pathogenesis of non-erosive gastro-oesophageal reflux disease. Medical therapy may be developed in future to enhance functional oesophageal epithelial defense.