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Ghrelin is a 28-amino-acid peptide predominantly produced by the stomach, while substantially lower amounts derive from other tissues including the pancreas. It is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R1a) and strongly stimulates GH secretion, but acylation in serine 3 is needed for its activity. Ghrelin also possesses other endocrine and nonendocrine actions reflecting central and peripheral GHS-R distribution including the pancreas. The wide spectrum of ghrelin activities includes orexigenic effect, control of energy expenditure, and peripheral gastroenteropancreatic actions. Circulating ghrelin levels mostly reflect gastric secretion as indicated by evidence that they are reduced by 80% after gastrectomy and even after gastric by-pass surgery. Ghrelin secretion is increased in anorexia and cachexia but reduced in obesity, a notable exception being Prader-Willi syndrome. The negative association between ghrelin secretion and body weight is emphasized by evidence that weight increase and decrease reduces and augments circulating ghrelin levels in anorexia and obesity, respectively, and agrees with the clear negative association between ghrelin and insulin levels. In fact, ghrelin secretion is increased by fasting whereas it is decreased by glucose load as well as during euglycemic clamp but not after arginine or free fatty acid load in normal subjects; in physiological conditions, however, the most remarkable inhibitory input on ghrelin secretion is represented by somatostatin as well as by its natural analog cortistatin that concomitantly reduce β-cell secretion. This evidence indicates that the endocrine pancreas plays a role in directly or indirectly modulating ghrelin secretion. As anticipated, ghrelin, in turn, is expressed within the endocrine pancreas, although it is still matter of debate if it is expressed by β-, α-, or non-α/non-β cells. Moreover, GHS-R1a expression in the pancreas has been demonstrated by many authors. Some impact of synthetic GHS on insulin secretion and glucose metabolism had been reported in both animal and human studies. Depending on dose and experimental conditions ghrelin has been shown able to inhibit or stimulate insulin secretion in animals. In humans, ghrelin administration is followed by transient inhibition of insulin levels that surprisingly follows persistent increase in plasma glucose levels suggesting that ghrelin would also directly or indirectly activate glycogenolisis. Current studies indicate that ghrelin also blunts the insulin response to arginine but not that to oral glucose load in humans. These acute effects of ghrelin are independent of any cholinergic mediation and are not shared by synthetic, peptidyl GHS indicating they are likely mediated by a non-GHS-R1a receptor. These acute effects of ghrelin on insulin secretion would be short-lasting, and it has to be remembered that long-term treatment with synthetic non peptidyl GHS in healthy elderly subjects was followed by insulin resistance. In all, it is already clear that ghrelin has remarkable impact in modulating insulin secretion and glucose metabolism. Insulin and ghrelin secretions seem linked by a negative functional relationship that strengthens the hypothesized role of ghrelin in participating in the management of the neuroendocrine and metabolic response to variations in energy balance.