The symptoms of dyspepsia, which may include epigastric pain, heartburn, bloating, and early satiety, defy diagnosis in as many as 50% of patients, even after endoscopy and other appropriate studies. In the other half of patients, such causative disorders as gastroesophagel reflux disease (GERD), peptic ulcer disease, cholecystitis, pancreatitis, and gastric cancer may be diagnosed. Despite controversy regarding the selection of therapy, empiric treatment is common for apparent idiopathic dyspepsia. Histamine 2-receptor antagonists, proton pump inhibitors (PPIs), promotility agents, and coating agents have all been used as empiric therapy for dyspeptic symptoms. With empiric treatment, subsequent management is directed by the therapeutic response. In the absence of a definitive diagnosis, treatment is usually selected on the basis of the type and severity of symptoms, a thorough history and physical examination, and factors such as age and the presence of Helicobacter pylori infection. Five PPIs are currently available—lansoprazole, omeprazole, rabeprazole, pantoprazole, and esomeprazole—all with established efficacy in GERD and other acid-mediated disorders. The PPIs can be expected to be useful in certain patients with dyspepsia, and may be prescribed for patients who are found to respond to potent antisecretory therapy. Patients' concern about their symptoms, practical considerations, and restrictions imposed by managed care organizations may all affect the choice between empiric therapy and early endoscopy in patients with dyspepsia.