The permeability of the oral mucosa to organic solutes of different molecular volumes, oil-to-water distribution coefficients, and pKa was studied in an in-vivo system. The calculated permeability coefficients were independent of time of application and the concentration of the solutes, a finding consistent with transport by simple diffusion. The permeability of organic acids was pH dependent whereas permeability to compounds with a degree of ionization that did not change over the pH range was not affected by pH. Increasing the chain length from two to eight carbons in an organic acid series resulted in an increase of both the oil-to-water distribution coefficient and the permeability coefficient; the permeability coefficient was decreased by the addition of oxygen in the form of hydroxyl groups. These results indicate that there is similarity in the way that lipid-soluble substances diffuse across oral mucosa and other lipid membranes. Results using compounds with oil-to-water distribution coefficients less than that of water suggest that these compounds traverse the oral mucosa by two additional routes. One, for compounds with molar volumes less than 80 cm3/ml, is via pores; whereas, the second, utilized by larger compounds, is probably by an intercellular route.