Epithelialization is a critical process in wound healing, involving the restoration of the epidermis after injury through keratinocyte activity. Keratinocytes, the major cell type in the epidermis, play a central role in this process, including cellular mechanisms and interactions with other cell types involved in wound healing. Recent advances highlight the importance of epidermal stem cells, keratinocyte immune function, and the epidermis as an independent neuroendocrine organ. Novel mechanisms of gene expression regulation, such as microRNAs and histone modifications, are also discussed. Epithelialization is essential for successful wound closure, and its failure is a hallmark of chronic wounds. Keratinocytes maintain the skin barrier and are crucial for restoring it after injury. The process involves keratinocyte migration, proliferation, and differentiation, which are regulated by various factors, including growth factors, cytokines, and integrins. The role of epidermal stem cells (ESCs) in wound healing is significant, with different niches contributing to tissue repair. ESCs are involved in the regeneration of the epidermis, and their function is regulated by various signaling pathways. Keratinocyte migration and proliferation during epithelialization are influenced by factors such as growth factors, cytokines, and integrins. The process of migration involves the breakdown of cell-cell and cell-substrate contacts, allowing keratinocytes to move into the wound area. This is modulated by various signaling pathways, including those involving PKC, Slug, and integrins. The expression of specific keratins, such as K6, K16, and K17, is upregulated during migration, contributing to the viscoelastic properties of migrating cells. Keratinocyte proliferation is regulated by growth factors, the extracellular matrix (ECM), and integrins. The availability of growth factors and the degree of cell differentiation influence keratinocyte proliferation. In chronic wounds, keratinocytes exhibit hyperproliferation and altered differentiation, contributing to nonhealing. The role of miRNAs and epigenetic modifications in regulating gene expression during epithelialization is also discussed, highlighting their importance in both normal and impaired wound healing. The epidermis functions as a neuroendocrine organ, producing hormones, neuropeptides, and neurotransmitters that influence wound healing. Keratinocytes express receptors for various hormones and can synthesize hormones that affect wound healing. Sex hormones, such as estrogen and testosterone, play a role in regulating skin turnover and wound healing. The balance of these hormones is crucial for proper wound healing. Keratinocyte immunity during epithelialization involves the recognition of pathogens and the production of antimicrobial peptides (AMPs), such as cathelicidins and β-defensins. These AMPs are critical for wound closure and epithelialization. However, their expression is deregulated in chronic wounds, contributing to impaired healing. The role of Toll-like receptors (TLEpithelialization is a critical process in wound healing, involving the restoration of the epidermis after injury through keratinocyte activity. Keratinocytes, the major cell type in the epidermis, play a central role in this process, including cellular mechanisms and interactions with other cell types involved in wound healing. Recent advances highlight the importance of epidermal stem cells, keratinocyte immune function, and the epidermis as an independent neuroendocrine organ. Novel mechanisms of gene expression regulation, such as microRNAs and histone modifications, are also discussed. Epithelialization is essential for successful wound closure, and its failure is a hallmark of chronic wounds. Keratinocytes maintain the skin barrier and are crucial for restoring it after injury. The process involves keratinocyte migration, proliferation, and differentiation, which are regulated by various factors, including growth factors, cytokines, and integrins. The role of epidermal stem cells (ESCs) in wound healing is significant, with different niches contributing to tissue repair. ESCs are involved in the regeneration of the epidermis, and their function is regulated by various signaling pathways. Keratinocyte migration and proliferation during epithelialization are influenced by factors such as growth factors, cytokines, and integrins. The process of migration involves the breakdown of cell-cell and cell-substrate contacts, allowing keratinocytes to move into the wound area. This is modulated by various signaling pathways, including those involving PKC, Slug, and integrins. The expression of specific keratins, such as K6, K16, and K17, is upregulated during migration, contributing to the viscoelastic properties of migrating cells. Keratinocyte proliferation is regulated by growth factors, the extracellular matrix (ECM), and integrins. The availability of growth factors and the degree of cell differentiation influence keratinocyte proliferation. In chronic wounds, keratinocytes exhibit hyperproliferation and altered differentiation, contributing to nonhealing. The role of miRNAs and epigenetic modifications in regulating gene expression during epithelialization is also discussed, highlighting their importance in both normal and impaired wound healing. The epidermis functions as a neuroendocrine organ, producing hormones, neuropeptides, and neurotransmitters that influence wound healing. Keratinocytes express receptors for various hormones and can synthesize hormones that affect wound healing. Sex hormones, such as estrogen and testosterone, play a role in regulating skin turnover and wound healing. The balance of these hormones is crucial for proper wound healing. Keratinocyte immunity during epithelialization involves the recognition of pathogens and the production of antimicrobial peptides (AMPs), such as cathelicidins and β-defensins. These AMPs are critical for wound closure and epithelialization. However, their expression is deregulated in chronic wounds, contributing to impaired healing. The role of Toll-like receptors (TL