Pharmaceutical companies have searched for years for a drug for the treatment of obesity that could safely augment thermo-genesis and thus increase energy expenditure. The discovery of a third β-adrenergic receptor, the β3or atypical adrenoceptor, and the discovery in small mammals that drugs targeted to this receptor prevent or correct obesity (and unexpectedly hyperglycemia as well) have intensified this search. As yet no fully selective or active β3adrenoceptor agonist against the human receptor has been available for testing. Several partially selective and active agonists have been tested in humans, with encouraging effects on thermo-genesis and insulin sensitivity. All have suffered from problems of toxicity, lack of selectivity for the human β3adrenoceptor resulting in unacceptable tachycardia (β1effect) or tremor (β2effect) or lack of full activity at the human β3adrenoceptor. A recently introduced drug, CL 316,243, is in phase II clinical trials. It is a selective, but only partial, agonist for the human B3AR. The important question is whether the remarkable effects of these drugs on obesity and diabetes in small mammals will translate to the human conditions. As yet this question cannot be answered because of differences in the expression, activity, and pharmacology of β3adrenoceptors between small mammals and large mammals (including humans) and because of the lack of an available fully selective and active agonist against the human receptor.