The skin represents the largest and most accessible organ of the body, and it is subjected to numerous aggressions such as infections, physical wounds and diseases. After a moderate-intensity injury, the intrinsic regenerative mechanisms of the skin lead to restoration of the tissue integrity. However, in some pathological cases such as chronic wounds and extensive burns, the healing capacity of the tissue is overwhelmed. In order to resolve these injuries, innovative therapies based on miRNAs as well as paracrine and trophic activities of stem cells combined with biomaterials are currently being developed. This chapter begins with a description of skin biology, followed by the main stages of wound healing including the key cells and molecules involved. Next, we describe the most studied miRNAs relevant for chronic wounds therapies and the proposed methods of delivery. Regarding cellular therapy, the main adult differentiated cells as well as stem cells available from different sources, are presented. Then, we address the commercially available skin substitutes and also the latest innovative approaches, including 3D bioprinting, for combining biomaterials with the activity of the cells previously described, in order to promote wound repair and regeneration. This chapter concludes with current challenges and future perspectives regarding the use of stem cells for skin regeneration.