In the adult interfollicular epidermis (IFE), tissue renewal is driven by heterogeneous groups of basal cells that occupy and maintain two distinct spatial domains. Although these IFE domains are initially established during skin development, the basal cells’ behaviors are largely influenced by the physiological demands of the IFE domains they occupy. This distinction is especially pronounced in the mouse tail and human IFE, where the tissue regeneration rates vary as a result. The first part of this dissertation elucidates the molecular and cellular states of different basal cell populations occupying binary IFE domains via marker gene expressions and single-cell transcriptomics. SOX6 is one such marker gene highly enriched in the basal cells occupying a more environment-exposed domain. The findings highlight the molecular and structural similarities between mouse tail and human IFE, where two distinct branches of basal cells merge into a single differentiation pathway, reflecting the structural binary organization of IFE. Further investigation of SOX6 functions reveals the differential UVB response between the two domains – basal cells of a more exposed domain upregulate SOX6 as an adaptive mechanism to promote their proliferation and survival upon increased UVB stress. Moreover, a subsequent study utilizing newly generated Sox6-CreERT2 knock-in mice emphasizes the upregulation of various stress response pathways by these non-self-renewing latent progenitors, confirming their increased environmental exposure. Surprisingly, a long-term loss of SOX6 leads to a hyperpigmentation phenotype, and a new SOX6 role in inhibiting keratinocyte-melanocyte paracrine signaling during homeostasis is revealed. Upon UVB-induced SOX6 downregulation, melanogenesis-promoting paracrine signaling genes are upregulated, resulting in melanocyte migration to and activity in UVB-exposed IFE domains. Thus, these findings not only uncover the SOX6 functions in promoting keratinocyte proliferation and survival but also in coordinating keratinocyte-melanocyte communication. SOX6 is also highly expressed by the primed hair follicle stem cells (HFSCs) and their rapidly expanding progenitors in HFs, the absence of which leads to delayed hair growth. The SOX6 loss results in perturbation of cell survival in primed HFSCs and cell proliferation and DNA damage protection in matrix cells. Thus, this dissertation highlights the versatile role SOX6 plays in adult skin maintenance during homeostasis.