The motor response of histamine on the lower esophageal sphincter and the receptors involved were investigated on isolated preparations from rats, guinea pigs and humans. Histamine exerted a spasmogenic effect through excitation of H1-receptors. H1-receptor selective agonists in the rat but not in the guinea pig seem to act through release of prostaglandin-like substances. Apparently H2-receptors, whose stimulation causes relaxation of the sphincter, do not occur in the LES of rat and human whereas they are present in the guinea pig. H2-receptor antagonists exerted different and sometimes opposite effects and this suggests that their actions depend on the specific molecules and not on the H2-receptor blockade. The significance and the importance of the above findings are discussed.