Currently available medications for gastroesophageal reflux disease (GERD) vary in mechanisms of action from neutralization or suppression of gastric acid to improving underlying upper gastrointestinal dysmotility. This article reviews the clinical efficacy of pharmacological agents used to treat GERD and provides a rationale for considering a primary prokinetic approach to antireflux treatment which will be applicable to many patients. Treatment trials in acute GERD have demonstrated unexpectedly prolonged maintenance of high esophageal pH with tablet and liquid antacid formulations. However, there are no well-designed placebo-controlled trials of antacids for esophageal mucosal healing. H2 receptor antagonists (H2RAs) at conventional doses relieve reflux symptoms in at least 50% of reported series of GERD patients, and they can also provide endoscopic healing in 27-45% of the cases. Therapy with more potent acid-suppressive agents such as proton pump inhibitors (PPIs) may lead to improved symptomatic relief and to superior healing compared with H2RA therapy, especially in those patients with more advanced erosive esophagitis. Promotility agents, particularly cisapride, offer symptom relief and healing rates which are quite similar to standard H2RA treatment. GERD tends to be a chronic and relapsing condition. Cisapride has been shown to be quite effective in maintaining remission in GERD patients, including endoscopic remission in the lesser degrees of esophagitis. This may be accomplished with relatively low and cost-effective dosing in many individuals. For the small proportion of patients who manifest severe grades of esophagitis, PPI therapy is associated with lower relapse rates than either H2RA or prokinetic treatment. Overall, a strong case can be made for the empirical selection of promotility therapy for the large numbers of GERD patients who do not have documented severe erosive disease.