We have measured on isolated epithelia of Rana skin the amount of tissue sodium that equilibrates with the sodium present in the solution in contact with the outside surface. Only about 12 % of the sodium in the tissue equilibrated with outside sodium. Antidiuretic hormone (0.1 u/ml) and ouabain (10 -4 mol l -1 ) had no effect on the amount of cell sodium that equilibrated with outside sodium. We have also studied with the electron microscope the localization of the permeability barriers of frog skin epithelium using as tracers ruthenium red and colloidal and ionic lanthanum. Our observations indicate that there are two barriers to diffusion in frog skin epithelium. The first is at the s. corneum, the second at the s. granulosum. Of these, the first is the least selective. In other experiments the effects of acetazolamide and amiloride on active transport of both sodium and chloride were determined. Acetazolamide (10 -4 mol l -1 ) blocked chloride transport without affecting sodium transport. Amiloride (10-4 mol l-1) blocked sodium transport and did not modify chloride transport. These results and others available in the literature are used to raise some defined questions on the relationship between structure and function and the coupling of ion fluxes in frog skin.