The historical model for the agonistic binding site on the histamine H2-receptor is based on a postulated activation mechanism: it has been suggested that the histamine monocation binds to the histamine H2-receptor via the formation of three hydrogen bonds. The cationic ammonium group in the side chain and the -NH- group in the tau-position of the imidazole act as proton donors, whereas the =N- atom in the pi-position of the imidazole acts as a proton acceptor. Participation of the ammonium group in H-bonding with a presumed negative charge on the receptor leads to a decrease in positive charge, which is thought to induce a tautomeric change in the imidazole ring system from N tau-H to N pi-H. A consequence of this tautomeric shift is the donation of a proton from the receptor to the agonist on one side, while on the other side a proton is donated from the agonist to the receptor. The propose tautomeric shift has been suggested to trigger the H2-stimulating effect. However, this model for the constitution of the agonistic binding site and the accessory activation mechanism cannot explain the weak histamine H2-activity of beta-histine and the activity of several other recently synthesized H2-agonists. Based on a thorough literature study and with the aid of molecular electrostatic potentials (MEPs) we demonstrate that the sulphur atom present in histamine H2-agonists as dimaprit and 2-amino-5-(2-aminoethyl)thiazole does not function as a proton acceptor, which implicitly means that a tautomeric shift is not a prerequisite for H2-stimulation. As a consequence, the model for the agonistic binding site is adjusted, resulting in a strong resemblance to the nature and orientation of the amino acids constituting the catalytic triad in serine proteases. Within this concept, the N pi-H tautomer of histamine is the biologically active form, in contrast with the existing model in which the N tau-H tautomer is the active form.