Non-healing chronic skin ulcers are considered a major biological, psychological, and financial burden for both patients and health systems. Multidisciplinary endeavors are required to address this refractory disease, in order to find definitive solutions that lead to improved living conditions. Diabetes, venous stasis, arterial insufficiency, pressure and radiation are common risk factors associated with chronic wounds. Unfortunately, the cured state for these wounds has a high relapse rate, which adversely affects the patient's quality of life. Nevertheless, advances on regenerative medicine have allowed the development of cell-based therapies that promote wound healing by increasing cell migration and differentiation. Particularly, mesenchymal stem cells (MSCs) and their acellular derivatives have emerged as an attractive therapeutic agent in various diseases, including chronic skin ulcers, due to their role in immunomodulation and tissue regeneration. In this review discusses the characteristics of MSCs as well as their regenerative properties and their action mechanisms on wound healing. Finally, the perspectives of MSCs and their acellular derivatives in clinical chronic skin ulcer therapy are also explored.