Although β₃-adrenoceptor (β₃AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and receptor pharmacology. β₃AR agonists, some of which also stimulate other βARs in humans, selectively stimulate fat oxidation in rodents and humans. This appears to be why they improve insulin sensitivity and reduce body fat whilst preserving lean body mass. Regulatory authorities ask that novel anti-obesity drugs improve insulin sensitivity and reduce mainly body fat. Drugs that act on different targets to stimulate fat oxidation may also offer these benefits. Stimulation of energy expenditure may be easy to detect only when the sympathetic nervous system is activated. Leptin resembles β₃AR agonists in that it increases fat oxidation, energy expenditure and insulin sensitivity. This is partly because it raises sympathetic activity, but it may also promote fat oxidation by directly stimulating muscle leptin receptors. The β₁AR and β₂AR can, like the β₃AR, display atypical pharmacologies. Moreover, the β₃AR can display variable pharmacologies of its own, depending on the radioligand used in binding studies or the functional response measured. Studies on the β₃AR demonstrate both the difficulties of predicting the in vivo effects of agonist drugs from in vitro data and that there may be opportunities for identifying drugs that act at a single receptor but have different profiles in vivo.