This comprehensive review focuses on the pivotal role of keratinocytes in epithelialization, the process of restoring the epidermis after injury. The review covers recent advances in understanding the cellular processes and mechanisms of keratinocyte regulation during re-epithelialization, including the involvement of epidermal stem cells, immune function, and the epidermis as an independent neuroendocrine organ. It also discusses novel mechanisms of gene expression regulation, such as microRNAs and histone modifications, which are crucial for re-epithelialization. The review highlights that epithelialization is essential for successful wound healing and is impaired in chronic wounds. Understanding the epithelialization process will lead to the development of novel therapeutic approaches to promote wound closure. The review emphasizes the complex interactions between keratinocytes and other cell types, such as fibroblasts, endothelial cells, and immune cells, during the wound healing process. Additionally, it explores the role of keratinocytes in immune responses and their ability to synthesize hormones, which can influence wound healing. The review concludes by discussing the potential of using cell therapies and targeting specific molecular pathways to improve wound healing.This comprehensive review focuses on the pivotal role of keratinocytes in epithelialization, the process of restoring the epidermis after injury. The review covers recent advances in understanding the cellular processes and mechanisms of keratinocyte regulation during re-epithelialization, including the involvement of epidermal stem cells, immune function, and the epidermis as an independent neuroendocrine organ. It also discusses novel mechanisms of gene expression regulation, such as microRNAs and histone modifications, which are crucial for re-epithelialization. The review highlights that epithelialization is essential for successful wound healing and is impaired in chronic wounds. Understanding the epithelialization process will lead to the development of novel therapeutic approaches to promote wound closure. The review emphasizes the complex interactions between keratinocytes and other cell types, such as fibroblasts, endothelial cells, and immune cells, during the wound healing process. Additionally, it explores the role of keratinocytes in immune responses and their ability to synthesize hormones, which can influence wound healing. The review concludes by discussing the potential of using cell therapies and targeting specific molecular pathways to improve wound healing.