This chapter reviews the biology of gastroesophageal reflux disease, relating pathophysiology to medical and surgical therapy. Various definitions of the disease are presented and workable criteria are developed to identify patients with the disease. The central importance of the lower esophageal high-pressure zone as a barrier to reflux is emphasized, along with an analysis of its biomechanical alteration in disease. The composition of the refluxed gastric juice is characterized in regard to its potential for mucosal injury. Evidence is provided that cardiac-type mucosa is an acquired sequel to acid-induced squamous mucosal injury in the terminal esophagus. A hypothesis regarding the process of intestinalization of cardiac-type mucosa to form Barrett's esophagus is presented. An integrated concept of the pathophysiology of gastroesophageal reflux disease is constructed. Practical concepts regarding the treatment of gastroesophageal reflux disease are developed, based on a review of studies on the natural history of the disease and the long-term outcome of therapy.