The epidermis is a self-renewing tissue. The balance between proliferation and differentiation processes is tightly regulated to ensure the maintenance of the stem cell (SC) population in the epidermis during life. Aging and cancer may be considered related endpoints of accumulating damages within epidermal self-renewing compartment. is a potent inhibitor of the G1/S-phase transition of the cell cycle. governs the processes of SC self-renewal in several tissues and its deregulation may result in aging or tumor development. Keratinocytes are equipped with several epigenetic enzymes and transcription factors that shape the gene expression signatures of different epidermal layers and allow dynamic and coordinated expression changes to finely balance keratinocyte self-renewal and differentiation. These factors converge their activity in the basal layer to repress expression, protecting cells from senescence, and preserving epidermal homeostasis and regeneration. Several stress stimuli may activate expression that orchestrates cell cycle exit and senescence response. In the present review, we discuss the role of regulators in human epidermal SC self-renewal, aging and cancer.