One in every three cancers diagnosed is a skin cancer. Oncoprotein Yes-associated protein (YAP) is a pivotal and highly conserved regulator of stem cells and organ size that is active in human cancer. We have recently generated a transgenic mouse model that expresses a constitutively active form of YAP protein mutant YAP2-5SA-ΔC in the basal epidermal cells, and survives postnatal life. YAP2-5SA-ΔC mice display hyperpigmentation, and a dramatic expansion of epidermal stem/progenitor cell populations in the interfollicular epidermis and in the hair follicle bulge. Wnt/β-catenin signaling is another pivotal regulator of epidermal and melanocyte stem/progenitor cell proliferation. We found that YAP and β-catenin co-localize in epidermal stem/progenitor cells, and found increased β-catenin activity in hyperproliferating epidermal stem cells of YAP2-5SA-ΔC mice. Interestingly, we also found that YAP and β-catenin co-localize in the nuclei of human skin cancers. Taken together, this work reveals the existence of a positive regulatory interaction between YAP and β-catenin in the regulation of epidermal stem/progenitor cell proliferation during normal skin homeostasis, which may be disrupted in the etiology of skin cancer.