Keratinocytes can be divided into stem cells, transit amplifying cells, and postmitotic differentiating cells. Epidermal stem cells can contribute to the maintenance of the epidermis via their self-renewing ability. It was suggested that cell-ECM interactions influence these interactions. Thus, strategies for manipulating cell-ECM interactions hold promise in controlling skin disease or preventing aging effects. It is possible that epidermal cells are under the control of surrounding environment. For decade, we have been studying the effects of environmental factors for interfollicular epidermal stem cells. The effect of dermal sheath cells (DSC) was found to be mediated by IGFBP-2. Furthermore, IFGBP-3 contributes survival of interfollicular epidermal stem cells in skin equivalent models. In addition, it was reported by us that adipose tissue derived stem cells have stemness regulating effects. All these findings clearly showed that stemness of interfollicular stem cells can be regulated by surrounding factors and these stem cell activators can be useful in controlling skin aging and skin disease. Recently, our results have been well applied for the development of anti-aging cosmetics. Then, “stem cell activator whether it is internal or external” will be promising strategy for the development of therapeutic or cosmetic agents.