Although the H2 subclass of histamine receptor has been revealed by classical pharmacological approaches, the direct identification of this adenylate cyclase-linked receptor has, despite much effort, remained elusive. Initial studies using 3H-metiamide and 3H-histamine and, subsequently, work from our own laboratory and others using 3H-cimetidine and 3H-ranitidine in various tissues, has shown the unsuitability of these ligands for labelling the H2 receptor. We report here our results using 3H-tiotidine, a more potent H2-antagonist than either cimetidine or ranitidine, and show that this ligand meets the criteria for labeling the H2 receptor in guinea pig cerebral cortex membranes.