In recent years, many new systemic medications have been developed as potential therapies for the patient with chronic GER and esophagitis. Despite these therapeutic advances, large numbers of GER patients continue to have chronic symptoms or unresolved complications. To some degree, this may relate to uncertainties regarding the pathogenesis of GER and its complications; i.e., is it primarily due to acid/pepsin injury or to primary motility disorders in the esophagus. Many new therapies are currently being developed, particularly those with the potential ability to enhance esophageal contractions--the prokinetic drugs. The main potential therapies of GER are discussed, including possible new acid suppression therapies, new anticholinergic drugs, new prokinetic drugs, and medications that might enhance the mucosal barrier. In addition, the more complex questions of effectiveness of chronic medical versus surgical therapy, and the use of combined medical therapies, are discussed.