In this investigation, we classified the site and mechanism of action of three penetration enhancers based on a two-layer diffusion model with the polar and nonpolar routes in the stratum corneum. 1-geranylazacycloheptan-2-one(GACH)increases the drug partitioning between the nonpolar route and aqueous vehicle, while d-limonene increases drug diffusivity in the nonpolar route. Oleic acid increases both partitioning and diffusivity of drugs in the nonpolar route. The simulation based on the analytical results revealed that the enhancement ratio has a bell-shaped relationship against the lipophilicities of drugs when an enhancer increases the diffusivity or partitioning of drugs in the nonpolar route. It was also shown that the amount of a drug in the skin increases with an increase in drug partitioning, while it dose not change so much with an increase in drug diffusivity. Further, a simulation revealed the effect of an enhancer on skin penetration of drugs is dependent on polarity of vehicles in the finite dose system.