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β₃-Adrenoceptors mediate several functions in rodents that could be beneficial for the treatment of obesity and type 2 diabetes. This includes promotion of insulin release from the pancreas, cellular glucose uptake, lipolysis, and thermogenesis in brown adipose tissue. In combination, they lead to a reduction of body weight in several rodent models including ob/ob mice and Zucker diabetic fatty rats. These findings stimulated drug development programs in various pharmaceutical companies, and at least nine β₃-adrenoceptor agonists have been tested in clinical trials. However, all of these projects were discontinued due to the lack of clinically relevant changes in body weight. Following a concise historical account of discoveries leading to such drug development programs we discuss species differences that explain why β₃-adrenoceptors are not a meaningful drug target for the treatment of obesity and type 2 diabetes in humans.