Melatonin, an indole formed enzymatically from L-tryptophan, is the most versatile and ubiquitous hormone molecule produced not only in all animals but also in some plants. This review focuses on the role of melatonin in upper portion of gastrointestinal tract (GIT), including oral cavity, esophagus, stomach and duodenum, where this indole is generated and released into the GIT lumen and into the portal circulation to be uptaken, metabolized by liver and released with bile into the duodenum. The biosynthetic steps of melatonin with two major rate limiting enzymes, arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT), transforming tryptophan to melatonin, originally identified in pinealocytes have been also detected in entero-endocrine (EE) cells of GIT wall, where this indole may act via endocrine, paracrine and/or luminal pathway through G-protein coupled receptors. Melatonin in GIT was shown to be generated in about 500 times larger amounts than it is produced in pineal gland. The production of melatonin by pineal gland shows circadian rhythm with high night-time peak, especially at younger age, followed by the fall during the day-light time. As a highly lipophilic substance, melatonin reaches all body cells within minutes, to serve as a convenient circadian timing signal for alteration of numerous body functions.. Following pinealectomy, the light/dark cycle of plasma melatonin levels disappears, while its day-time blood concentrations are attenuated but sustained mainly due to its release from the GIT. After oral application of tryptophan, the plasma melatonin increases in dose-dependent manner both in intact and pinealectomized animals, indicating that extrapineal sources such as GIT rather than pineal gland are the major producers of this indole. In the upper portion of GIT, melatonin exhibits a wide spectrum of activities such as circadian entrainment, free radicals scavenging activity, protection of mucosa against various irritants and healing of various GIT lesions such as stomatitis, esophagitis, gastritis and peptic ulcer. This review concentrates on the generation and pathophysiological implication of melatonin in upper GIT.