The nature of drug agonism has been the central mystery of two conceptually different approaches: classical receptor theory, which does not require any knowledge of mechanism, and mechanistic theories, which do. Ligand-activated ion channel macromolecules that contain both the agonist receptor site and molecular machinery to generate a response present a unique experimental system with which to explore agonism and antagonism. Electrical recordings from one channel at a time offer phenomena and a perspective quite different from that usually encountered in studies of the drug-receptor interaction. This review describes patch-clamp recordings that illustrate the ligand-evoked behavior that gives rise to classical phenomena. A comparison of the channel currents recorded in the presence of different agonists reveals how these drugs act as full or partial agonists. At higher concentrations of agonist, the conformational and kinetic transitions that underlie desensitization can be observed. Receptor conformational changes induced by agonist and antagonist binding further expand our ideas about what these drugs do, and contribute to the growth of concepts that will further our understanding of drug agonism.