A pH-dependent model of agonist action for the histamine H2 receptor was developed by taking into account the different ionic states of the amino acid residues that constitute the agonist-binding pocket of the receptor. The model offers the possibility of examining diverse mechanistic pathways to yield the active form of the receptor according to the molecular structure of the ligand. The rationale is valid for either tautomeric or non-tautomeric agonists and provides new insight into the mechanism of receptor activation. The subsequent application of the operational model of agonism allows one to derive agonist concentration- effect relationships that may prove useful for both the simulation of agonist profiles under different physiological conditions and the estimation of the pharmacologic parameters of efficacy and potency. General principles involved in the formulation are expected to be valid for other G-protein-coupled receptors.