The homeostatic integrity of skin epidermis is maintained by a balance between keratinocyte proliferation, on one hand, and terminal differentiation combined with outward migration and shedding, on the other. Perturbation of this balance in favor of proliferation can result in hyperplasia and, potentially, tumorigenesis. We have previously described a reversible transgenic mouse model of epidermal neoplasia in which expression of an acutely regulatable form of Myc, MycER TAM, is targeted to epidermis via the involucrin promoter. In this model, sustained activation of MycER TAM induces a complex neoplastic lesion involving marked hyperplasia of less-differentiated suprabasal cells, angiogenesis and overt papillomatosis. Subsequent deactivation of MycER TAM triggers complete papilloma regression. Here, we provide evidence that Myc-induced papillomas are self-limiting because of the eventual differentiation of MycER TAM-expressing keratinocytes. Thus, keratinocyte differentiation eventually prevails over Myc-induced proliferation. We also show that regression of Myc-induced papillomas following MycER TAM deactivation occurs through a combination of growth arrest and irreversible differentiation. Finally, we demonstrate that transient deactivation of Myc is sufficient to expel keratinocytes irreversibly from the proliferative compartment and render them refractory to the mitogenic influence of subsequent Myc reactivation. Such observations illustrate the potential utility of even short-term inhibition of oncogenic lesions in the treatment of cancer.