In target organs, insulin switches substrate utilization from free fatty acids to glucose, a change that: (i) is oxygen-efficient; (ii) repletes glycogen stores; (iii) removes potentially toxic fatty acids; and (iv) restores intracellular potassium. During or after an ischaemic challenge, the insulin metabolic mode should protect cellular functions provided that insulin can reach the ischaemic tissue. Insulin, however, also exerts non-metabolic effects, such as membrane hyperpolarization, the stimulation of adrenergic activity, and inhibition of parasympathetic tone, which may counter its beneficial metabolic actions. The net balance between the favourable and unfavourable effects of insulin on ischaemic tissues depends on: (i) the dose-response of the various effects; (ii) the presence of insulin resistance; (iii) the coexistence of hyperglycaemia; and (iv) the stage of ischaemic tissue damage. At present, a role for glucose-insulin-potassium infusions in clinical practice seems to be clearly established in the case of diabetic patients with acute coronary syndromes, and in patients undergoing urgent or elective cardiac surgery. Its role as an adjunctive therapy in the management of myocardial infarction in non-diabetic individuals has been tested in several clinical trials; however, the evidence emerging from them is inconclusive.