Obesity is considered one of the risk factors for metabolic disorders such as diabetes mellitus. There is increasing evidence that obesity and diabetes are under the control of numerous cytokines and hormones, such as adiponectin and leptin. In addition, a number of studies have revealed that the brain functions play a role in the development of obesity and diabetes mellitus. Histamine and its receptors are classical inflammatory mediators in peripheral tissues and also function in the brain. The results of physiological and pharmacological studies revealed that brain histamine and its receptors are involved in the regulation of obesity and diabetes mellitus. Leptin has been shown to regulate obesity and diabetes partially via brain histamine and its receptors. In this review, we focused on the roles of brain histamine and its receptors in regulating obesity and diabetes mellitus.