The chapter characterizes differences in the recognition of agonists and antagonists by some neuronal receptors and describes a paradox of agonists, also stating the possible explanations. The paradox consists in smaller affinities of agonists to neuronal receptors, when compared with antagonists, despite the prominent biological effect of the former (agonists), as cGMP or G-protein activation, or ion channel gate opening. However, the measured free energy of agonist binding does not appear to be enough for performing the work of protein machinery. When the nicotinic receptor directly conjugates with an ion channel, the model for receptor activation is proposed, connecting agonist–receptor complex disruption to water permeation into the binding pocket after its conformational transformation. It is assumed that there are fast-transformation stages in receptor activation, which is not observed in experiments because of their high rates. Therefore, the measured agonist affinity might not catch the high-energy produced stages. For muscarinic and opioid receptors, the same fast-transformation stages also may exist.