The skin is a dynamic, regenerative organ capable of withstanding diverse internal and external stresses, supported by tissue-resident stem cells. A complex signaling network regulates interactions between epidermal stem cells, dermal cells, immune cells, and the extracellular matrix to maintain tissue integrity. Disruptions in these signaling pathways can impair cellular communication, alter stem cell lineage commitment, and compromise epidermal stem cell identity, ultimately resulting in a loss of coordinated tissue function. In this review, we highlight recent insights into three key signaling factors—metabolic, mechanical, and inflammatory cues—that regulate epidermal stem cell behavior during homeostasis, regeneration, and aging. We further discuss how dysregulation of these pathways contributes to pathological skin remodeling and explore emerging intervention strategies targeting signaling molecules to restore epidermal stem cell function and skin health.