1. The usefulness of nonanesthetics in the study of mechanisms of general anesthesia lies in the possibility to identify the unifying characteristics of molecular sites that are shared by the anesthetics but not by the structurally similar nonanesthetics. 2. In model membranes, pairs of structurally similar anesthetics and nonanesthetics showed distinctly different submolecular distributions. 3. This difference may be the underlying cause for the different anesthetic and nonanesthetic interaction with gramicidin A, a model transmembrane cation channel. 4. Generalization of our findings suggests that the nature of the sites, whether in lipids or proteins, must be neither extremely hydrophilic nor extremely lipophilic, but amphiphilic.