During the past few years, there has been a tremendous increase in our understanding of the histamine receptors. Important progress has been made in the development of H1-receptor agonists and the rationalization of H1-receptor-ligand interaction. The recent observation of constitutive H1- and H2-receptor activity has led to a reclassification of H1- and H2-antagonists. For the H3-receptor, a wide variety of selective and potent ligands are currently available and await clinical application. The recent cloning of the H3-receptor gene and the anticipated generation of transgenic mice will facilitate this development. Within the field of signal transduction, a previously unanticipated complexity has been unravelled. With the cloning of the H3-receptor gene, a similar complexity is to be expected.