The epidermis is the outermost protective cover of the human body. It constantly renews itself through the differentiation of epidermal stem cells or EpiSCs located in the basal layer. EpiSCs express integrins that bind to the underlying basement membrane. The EpiSCs-basement membrane interactions regulate the proliferation and differentiation of EpiSCs. EpiSCs self-renew and sequentially differentiate to form a multi-layered epidermis consisting of spinous cells, granular cells, and dead keratinized squames. Two models are used to explain EpiSC differentiation. In the hierarchical model, EpiSCs divide asymmetrically to form a proliferative daughter cell and a transit-amplifying or TA cell. The TA cells further differentiate into different epidermal cell types. In the stochastic model, each of the daughter cells will randomly either remain proliferative or form differentiated epidermal cells.