Dyspepsia, defined as pain or discomfort centered in the upper abdomen, affects an estimated 25% of the U.S. population each year; accounts for up to 5% of all visits to primary care physicians, and generates over $1.3 billion in prescription drug costs annually. In the majority of patients evaluated, no clear cause of symptoms can be identified, and the condition is termed functional or nonulcer dyspepsia (NUD). The pathophysiology of NUD remains unclear, but disturbances in gastrointestinal motility or sensation are often found. Clinically, NUD can be subdivided into dysmotility-like (in which discomfort, fullness, bloating, early satiety, or nausea [but not pain] predominate) or ulcer-like (in which epigastric pain is predominant). In ulcer-like NUD, antisecretory therapy is useful, but in dysmotility-like NUD, acid suppression is not superior to placebo. Cisapride accelerates gastric emptying and enhances gastric accommodation but probably does not blunt perception. Although cisapride relieves symptoms of dyspepsia without the adverse central nervous system effects often associated with metoclopramide, its cardiac toxicity has led to disuse. Antidepressants are of uncertain efficacy but are widely used. New prokinetics and other enteric neuromodulating agents are being tested in NUD and are likely to find an important place in clinical practice in the future.