The innermost (basal) layer of the skin epidermis consists of proliferative progenitors which give rise to multiple differentiating layers providing a barrier that keeps the inside of the body moist and protects the body from outside assaults by physical, environmental and biological factors. The epidermis is maintained throughout life through the proliferation of stem cells and differentiation of their progeny. Notch signaling pathway is a highly conserved molecular network that plays an essential role in cell fate determination during embryogenesis and also in postnatal life. Data from ongoing studies indicate that Notch signaling orchestrates the process of epidermal differentiation and proliferation through the sequential activity of different Notch ligands, receptors and downstream pathways.