Using monodansylcadaverine as a fluorescent, lysine-substrate analogue, alterations in the histochemical profile of transglutaminase activity during human and coal tar-induced rabbit ear comedogenesis were examined. When compared to the normal pilosebaceous follicles of both species, a marked increase in enzyme-specific fluorescence in the hyperplastic epidermal lining and in the epithelium of the sebaceous duct was observed in human and rabbit early lesions. In mature human open and closed comedones, an intact band of transglutaminase activity corresponding to the differentiating epidermal cell layers was seen to surround the lesion. In mature rabbit comedones this band of activity was most striking. In most lesions, transglutaminase activity was closely apposed to the plasma membrane of the differentiating keratinocytes, the site of cornified envelope formation. In normal human and rabbit interfollicular epidermis the cornified layer immediately above the fluorescent granular layer was histochemically inactive, while the surface stratum corneum showed an increase in activity. A similar phenomenon was observed in many comedones. This pattern of activity may relate to the process of desquamation. Finally, the changes in transglutaminase activity observed during comedogenesis suggest the possibility that inhibitors of transglutaminase could be useful in acne therapy.