Since the discovery of glucagon’s opposing actions to insulin, drugs targeting the inhibition of glucagon action have been pondered. In recent years, several attempts to generate small molecules or antibodies that impair glucagon action have been pursued as potential therapeutics for type 2 diabetes. In the current issue of Diabetes Care, Kazda et al.(1) summarize the outcomes of the phase 2a and phase 2b clinical trials of LY2409021, a small-molecule glucagon receptor antagonist (GRA). This is the largest and longest trial for safety and efficacy of a GRA ever performed. Importantly, LY2409021 does not produce side effects on cholesterol homeostasis that have impeded the progress of other small-molecule GRAs. Here, we place their success in perspective and discuss the advantages and concerns relating to glucagon-based therapeutics as this line of drugs comes closer than ever to achieving their clinical potential. In 1922, the first children with type 1 diabetes were treated with an insulincontaining pancreatic extract, preventing ketoacidosis and an insidious death. In addition to the discovery of insulin, the crew of Banting, Best, and Collip observed glucagon action, as they had noticed in their preclinical studies in canines that some of their crude insulin preparations would raise glucose levels in the dog briefly before glucose was lowered (2, 3). This glucose-raising peptide was termed “glucagon”(4) and subsequently purified and identified as a 29–amino acid peptide (5). In 1959, the development of the radioimmunoassay made it possible to quantify the two major glucoregulatory hormones, insulin (6) and glucagon (7). It was quickly established that glucagon was in fact a true hormone responsible for maintaining the glucose supply to the brain via increased glycogenolysis and gluconeogenesis. It has since been demonstrated that every form of diabetes is associated with hyperglucagonemia, the suppression of which eliminates hyperglycemia (8). After pancreatectomy, glucagon-producing α-cells proliferate in the fundus of the stomach, allowing for hyperglucagonemia (9). In other words, diabetes is a bihormonal disease rather than simply the result of insulin deficiency (10)(Fig. 1). It was further shown that glucagon-producing α-cells are topographically arranged for functional reasons with 91% of α-cells in the islets of Langerhans juxtaposed to β-cells. This close proximity permits insulin to tightly regulate glucagon secretion and precisely control the insulin-to-glucagon ratio in the healthy pancreatic islet. When insulin is present, the α-cells, juxtaposed to β-cells, receive the highest insulin concentration of any target cell in the body. The paracrine levels of insulin reaching α-cells have been estimated at between 2,000 and 4,000 μU/mL (11). This is almost impossible to achieve by administration of insulin into the periphery, which provides a substantial gap in our ability to treat diabetes effectively within the clinic. An alternative to higher doses of insulin for the treatment of hyperglycemia is to minimize the contributions of glucagon. Thus, the insulin-to-glucagon ratio is enhanced by minimizing the denominator and glucagon’s effects on the liver. Regulation of glucagon secretion occurs locally, within the islet, and via effects in the central nervous system (12). Insulin, γ-aminobyteric acid, and leptin are potent physiologic regulators that dampen glucagon secretion (13). In 1984, we conducted experiments that demonstrated the paracrine role of insulin on α-cell function (11). Using a potent anti-insulin neutralizing serum, we perfused normal pancreata and showed that when insulin inside the islet was neutralized, glucagon levels rose by 150% and …