The upper gastrointestinal tract displays two different functional states: the interdigestive or fasting state, and the fed state. The fasting state is characterized by a cyclical motor pattern, the migrating motor complex (MMC). The control of the MMC is incompletely understood. Plasma levels of the hormone motilin fluctuate in synchrony with MMC, but it is still controversial whether a motilin peak triggers the MMC or whether the MMC causes motilin release. We used the motilin agonistic properties of erythromycin to resolve this issue in man. Administration of a low dose of erythromycin induced a MMC which started from the gastric antrum, unaccompanied by a motilin peak. This finding argues against a release of motilin secondary to the MMC and supports our hypothesis that in man motilin peaks trigger the MMC. We observed that higher doses of erythromycin no longer induced a MMC, but stimulated antral contractility. The enteric nervous system is involved in the control of both the fasting and fed state at each level of the gastrointestinal tract. We hypothesized that the target for motilin to trigger the MMC is the enteric nervous system in the gastric antrum. Yet, no physiological data on antral enteric neurons were available. We performed the first electrophysiological study of myenteric neurons of the gastric antrum, revealing unique electrical and synaptic properties in comparison to other regions of the gastrointestinal tract. We confirmed the role of the enteric nervous system of the gastric antrum in the control of the MMC by directly demonstrating the presence of motilin receptors on a subpopulation of neurons. We demonstrated that endogenous and exogenous substances that stimulate (cholecystokinin, cisapride, erythromycin) or inhibit (norepinephrine, 5-hydroxytryptamine) gastric emptying all act on antral enteric neurons. These observations strongly support the hypothesis that the enteric nervous system in the gastric antrum plays a key role in the coordination of antral peristalsis and the regulation of gastric emptying. Finally, we hypothesized that the actions of erythromycin on motilin receptors on enteric neurons and intestinal smooth muscle offer a potential for therapeutic applications in gastrointestinal motility disorders. We confirmed this by demonstrating gastrointestinal motility stimulating activity of erythromycin in patients with diabetic gastroparesis.