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Glucagon assays employing specific radioimmunoassay (RIA) techniques are now widely used to characterize pathologic conditions where the effect of the excess or deficiency of glucagon on insulin actions might play a role. Glucagon excess counteracts the action of insulin on glucose metabolism by stimulating glycogenolysis and gluconeogenesis. In diabetes mellitus, hyperglycaemia is the consequence of the glycogenolytic and gluconeogenic effects of glucagon excess occurring in the setting of a relative insulin deficiency (i.e. Type 2 diabetes), whereas excess of glucagon and absent insulin levels are typical features of diabetic ketoacidosis. Although plasma glucagon levels of persons with diabetes are usually increased relative to the prevailing plasma glucose concentrations, it is a paradox that in those patients glucagon levels fail to rise when hypoglycaemia develops. Since glucagon release is considered the primary defence against insulin-induced hypoglycaemia, the defective response of glucagon to hypoglycaemia may favour the development of severe hypoglycaemia. Such defective response to hypoglycaemia in diabetes can be regarded as a condition of selective glucagon deficiency the mechanisms of which remain to be elucidated. It is expected that drugs that are able to reduce glucagon secretion in concert with strategies directed to recover glucagon secretion to hypoglycaemia might contribute to improve the overall glycaemic control in diabetes.