Skin undergoes everyday turnover while often challenged by injuries. The wound healing process in the skin is a dynamic sequence of events that involves various cell types and signaling pathways. Epidermal stem cells (EpdSCs), the tissue-resident stem cells in the skin tissue, are at the center of this complicated process due to their special ability to self-renew and differentiate. During this process, EpdSCs interact actively with the tissue microenvironment, which is essential for proper re-epithelialization and skin barrier restoration. This review describes the intricate interplays between EpdSCs and various components of their surroundings, including extracellular matrix/fibroblasts, vasculature/endothelial cells, and immune cells, as well as their roles in tissue repair.