The present study is aimed at thermodynamic and statistical mechanical analyses of the association of local anesthetics with lipids, phospholipid membranes, protein macromolecules and nerve cell membrane fragments. At physiological pH, the clinically used aromatic amine local anesthetics exist in positively charged quaternary amines and in uncharged tertiary amines. It is generally assumed that the uncharged species are lipophilic and the charged species and hydrophilic. However, these molecules contain hydrophobic benzene ring at the other end of the structure, and both species are amphiphilic. Our study showed that the solubility of uncharged molecules in organic solvents decreased when the dielectric constants of the solvents were less than 10, indicating the propensity of these molecules to accumulate at the membrane/water interface. We postulate that their actions may be exerted at the interface and both species are effective. Amphiphilicity rather than lipophilicity may be the key factor for their nerve blocking activities. We have formulated at statistical mechanical theory which separates the interaction energies of anesthetics at the interface into the membrane-anesthetic and anesthetic-anesthetic interactions. The former energy represents the lipid-drug interaction. Together with the studies which measure the temperature dependence of the association of local anesthetics to model macromolecules, the thermodynamic basis of the mode of action of local anesthetics will be explored.