Etiologically, gastroesophageal reflux disease (GERD) can be regarded as motility disorder: Although blocking acid is effective in the treatment of GERD, it does not overcome the underlying pathologic factors that allow acid, pepsin, and bile to reflux into the esophagus. Prokinetic agents address the upper gastrointestinal motility disturbances contributing to GERD and, thus, have an important role in the short- and long-term medical management of reflux esophagitis. This paper discusses the rationale for the effectiveness of pharmacologic modulation by reviewing current concepts and postulated theories about the mechanisms underlying the neuromuscular abnormalities. The multifactorial aspects of GERD are addressed and the potential for tailoring medical therapy also emphasized.