The description of drug effects on receptor proteins is based on models and equations used to describe mass-action kinetics of molecules and inert surfaces. These models provide an adequate description of drug affinity, that is, how well a molecule binds to a receptor protein, but the way in which ligands change receptor populations to impart signals to cells remains to be determined. In the first of two articles, Terry Kenakin discusses a basic question in receptor pharmacology, namely the nature of ligand efficacy.