With the detection of the third histamine receptor subtype (H3), the neurotransmitter function of histamine could be established. Histamine H3-receptors located on histaminergic neurons control the synthesis and liberation of histamine by acting as autoreceptors and the release of a number of other neurotransmitters by acting as heteroreceptors. The first potent and selective agonist was (R)-α-methylhistamine. Stereoselectivity of the chain-branched histamine derivatives was high with the monomethylated and was even higher with the (R)-α,(S)-β-dimethylated derivative. These compounds are excellent pharmacological tools for H3-receptor-dependent investigations. Their pharmacodynamic advantages were not obvious when (R)-αmethylhistamine was tested in vivo in humans because of some pharmacokinetic disadvantages overcome by prodrug formation.