The effects on motilin release of various stimuli including an ordinary hospital lunch and ingestion of equicaloric amounts of protein (steamed cod), fat (double cream), or carbohydrate (glucose solution), and intraduodenal instillation of acid (0.1M HCl) and alkali (0.3M tris buffer, pH 10.2) have been investigated in healthy volunteers. Duodenal acidification resulted in a 90% rise of plasma motilin while after intraduodenal instillation of alkali motilin fell. No significant change was seen after a normal hospital lunch and the protein meal, and a small fall was observed after glucose. By contrast, after ingestion of 60 g fat motilin showed a peak increase of 65% at 30 minutes and was still significantly elevated at 60 minutes. Exogenous motilin has been reported to delay gastric emptying and this is also seen after duodenal acidification and fat ingestion. We conclude that motilin may be released physiologically by these stimuli and mediate their effects on gastric emptying in man.