Atypical antipsychotics AAP are prescribed to millions of patients with neuropsychiatric disorders. Although AAP can ameliorate mental dysfunctions, they have serious metabolic side-effects such as weight gain, the metabolic syndrome, and increased risk of diabetes and cardiovascular disease. The current dogma is that the metabolic side effects of AAP are attributed to their action on neuronal circuits the brain. However, we discovered expression of functional dopamine and serotonin receptors in human and rodent adipocytes and found that these receptors are targeted by AAP. In vivo studies with rats and in vitro studies with human adipocytes revealed multiple direct effects of AAP on adipose tissue. These include increased food intake, fat accumulation, enlargement of adipocytes, alterations in key metabolic genes, changes in the secretion of leptin and adiponectin, suppression of basal and isoproterenol-stimulated lipolysis, and increased preadipocyte proliferation. We conclude that AAP-induced metabolic dysregulation is caused, in part, by their direct action on adipose tissue, presumably via local dopamine and serotonin receptor subtypes.