Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). AG acts on the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have gluco-regulatory action, which adds an additional layer of complexity to ghrelin's regulation of glucose metabolism. This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT) with specific emphasis aimed toward distinguishing AG vs dAG action.