It has long been thought that the alpha cells and its secretory products play an important role solely in maintaining euglycemia and preventing hypoglycemia through a contradictory action to the B cell’s insulin. The α-cell function is tightly regulated by various physiological inputs including systemic energy status, central and autonomic nervous systems, and the endocrine system. It is also an important amino acid sensor, glucagon blockade suppresses hepatic amino acid catabolism and increases the serum amino acid level. In addition to those controllers, the intra-islet microenvironment, where α-cells are located, has been recently revealed to be important in the regulation of the various cellular secretory functions including the overlapping of glucagon and insulin secretion through a... precise cell-cell crosstalk. Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis, alpha and B cells are closely positioned on the sides of their blood supply where acetylcholine acts as the paracrine communicator of signals inside the islets. Recently, it has been demonstrated that blocking acetylcholine esterase increases insulin secretion. Moreover, it has also been suggested that glucagon is not exclusively a counter-regulatory hormone that elevates blood glucose levels, in contrast it can cause hypoglycemia conditioned by the presence of intact B cells and a functional GLP-1R (glucagon-like peptide 1 receptor). These data argue for glucagon agonism in modern management of T2DM. Alpha-cells also, have been shown to be able to trans-differentiate into β-cells only in the presence of insulin-positive cells with α-cell origin in the lineage tracing analyses, confirming the role of α-cells as a source of β-cell regeneration. The article reviews the updated knowledge about the functions of the alpha-cells and its role in the paracrine control of islet cell secretions and the future therapeutic potentials.