The interaction of opiate molecules (buprenorphine, codeine, dextromethorphan, diprenorphine, etorphine, meperidine, methadone, morphine, and naloxone) with lipids (phosphatidylcholine, phosphatidylinositol, phatidylinositol, phosphatidylserine, and cholesterol) by using liposomes and monomolecular layers as membrane models is described. The ability of opiates to induce leakage of carboxyfluorescin from liposomes is highly dependent on the hydrophobicity of the opiate molecules. Buprenorphine and etorphine increased the membrane permeability in all the experiments. On the contrary, naloxone, morphine, and codeine only caused a slight release of the entrapped dye in the presence of acidic phospholipids. Moreover, the leakage of carboxyfluorescein is directly related to the concentration of drug in the incubation media. Studies of the kinetics of the surface penetration of these molecules into monolayers of phospholipids were performed. Again, in this system, buprenorphine and etorphine exhibited stronger interactions than the most hydrophilic opiates. Nevertheless, in these experiments, differences among the opiate molecules are not so high as in the liposomes. The time course of the penetration of all of these molecules in the monolayers fits the Lineweaver-Burk equation. This fact suggests a lack of specific interactions and the predominance of hydrophobic factors. Moreover, the high percentage of release of entrapped dye caused by some opiate molecules suggests a possible toxic side-effect for these agents.