The alpha(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. alpha(2A)-Adrenoceptors on pancreatic beta-cells inhibit insulin secretion, and alpha(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human alpha(2A)-adrenoceptor gene polymorphisms that influence alpha(2A)-adrenoceptor expression and function have been described. Increased alpha(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of alpha(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished alpha(1)- and beta-adrenoceptor activation. alpha(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active alpha(2A)-adrenoceptors on pancreatic beta-cells, but may also enhance sympathoadrenal output. In addition, alpha(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The alpha(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated alpha(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent alpha(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, alpha(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and alpha(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on alpha(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.