The development of highly potent and selective ligands for the characterization of histamine H3-receptors is reviewed. In the field of agonists stereoselectively methylated derivatives of the natural ligand are found to have the desired pharmacodynamic properties. Pharmacokinetic properties could be improved by forming bioreversible azomethine prodrugs of the primary amine with benzophenone derivatives. In the antagonist field a number of new leads belonging to different chemical classes are discovered. Potential compounds for drug development are identified. The radiolabelled probe [125I]iodoproxyfan shows high potency and selectivity in functional and binding studies. It is a useful compound for binding assays as well as for the detection and localization of histamine H3-receptors.