Methotrexate, 5-fluorouracil (5-FU), and 6-mercaptopurine (6-MP) have been tested for action on epidermal structures following topical application. 5-FU and 6-MP inhibit rabbit hair regrowth, and 5-FU applied to human skin under suitable occlusive dressings produces erosion and pigmentation of normal skin and erosion and clearing of psoriatic plaques. These processes have been studied microscopically, showing specific effects on epidermal cells with little inflammatory reaction. Methotrexate has shown no action in these situations, and the possible reasons for this are discussed.