Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross-talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident γδT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases.