Cells within epithelial tissues, such as the skin and intestine, undergo high rates of turnover and require constant renewal to maintain organ homeostasis. Tissue-resident epithelial stem cells have the capacity to self-renew and differentiate to replenish senescent or damaged cells. The balance between epithelial stem cell proliferation and cell fate determination can be regulated by specific transcription factors. For example, p63/TP73L is thought to be a general regulator of epithelial stem cell self-renewal capacity. In specific epithelial stem cell populations, such as the intestine and hair follicle, SOX9 is important for cell differentiation. Increasing evidence suggests that precise control of transcription factor expression levels can affect whether an epithelial stem cell proliferates or differentiates. Consistent with this observation, deregulated transcription factor activation is associated with uncontrolled epithelial stem cell proliferation and the progression of carcinoma.