Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter. In the present article we review current evidence pointing at an important role of histamine in the regulation of appetite and metabolism. Studies using both knockout mouse models as well as pharmacological studies have revealed that histamine acts as an anorexigenic agent via stimulation of histamine H(1) receptors. One effect of histamine in the regulation of appetite is to act as a mediator of the inhibitory effect of leptin on appetite. It seems that histamine may attenuate and delay the development of leptin resistance in high-fat-diet-induced obesity. Furthermore, histamine may also act to accelerate lipolysis. Based on the current evidence of the involvement of histamine in the regulation of body weight, the histaminergic system is an obvious target for the development of pharmacological agents to control obesity. At present, H(3) receptor antagonists that stimulate the histaminergic system may be the most promising histaminergic drugs for antiobesity therapy.