Glucagon was discovered in 1923 as a contaminant of early insulin preparations, and its hormonal status was not established until its structure was established in the 1950 s and when the first radioimmunoassay was developed by Roger Unger, providing information about its secretion. Its role in hepatic glucose production was soon established and it was proposed as an essential factor in diabetic hyperglycemia. However, even today a number of issues remain unsolved. For instance, the assays for glucagon are not straightforward, although the development of sandwich ELISAs allowed reasonably accurate measurements also in rodents. The tools for evaluation of glucagon physiology include pancreatectomy, but studies in both humans and experimental animals pointed towards extrapancreatic sources of glucagon. It was demonstrated that glucagon receptor knockout animals do not develop diabetes upon destruction of their beta cells with streptozotocin. However, in patients with type 1 diabetes, glucagon antagonists do not normalize glucose levels; but antagonists do lower glucose levels in patients with in type 2 diabetes. Recent studies in animals and humans have confirmed the essential role of glucagon in glucose metabolism, but have suggested that it may be at least equally important for amino acid and lipid metabolism. In spite of the 100 years, glucagon research is very much alive.