The interactions of phenmelrazine hydrochloride, levarterenol bitartrate, d-amphetamine sulfate and fenfluramine hydrochloride with a spread monolayer of lecithin, cephalin and cholesterol have been measured surfacc pressure and surface potential. The surface pressure data indicate that penetration is a function of the relative hydrophobicilies of the compounds. However, the effect of drug concentration in the subphase and the surface potential data demonstrate that polar head group interactions play an important role in determining the structure of the membrane. The expansion of the monolayer at constant pressure follows in the same order as the Hydrophobie properties of the drugs but only fenflurdminc-contributed expansion was sensitive to the lateral surface pressure of the monolayer. Use of the multicomponenl lipid monolayer for interaction studies provides a high structured model of a membrane which may be warranted in some instances.