Methods for preventing damage to the epidermis during PDT induced using a pre-photosensitizing agent are provided. The methods of the present invention utilize spatial confinement to control formation of a photoactive species from a topically-applied pre-photosensitizing agent. In one embodiment, thermal inhibition is used to prevent the metabolism of a pre-photosensitizing agent in epithelial tissue surrounding a treatment site. In another embodiment, a chemical inhibitor can be applied to the epithelial tissue to inhibit the conversion of a pre-photosensitizing agent into a phototoxic species.