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Over the last century, the clinical management of severe skin burns significantly progressed with the development of burn care units, topical antimicrobials, resuscitation methods, early eschar excision surgeries, and skin grafts. Despite these considerable advances, the present treatment of severe burns remains burdensome, and patients are highly susceptible to skin engraftment failure, infections, organ dysfunction, and hypertrophic scarring. Recent researches have focused on mesenchymal stromal cell (MSC) therapy and hold great promises for tissue repair, as reported in several animal studies and clinical cases. In the present review, we will provide an up-to-date outlook of the pathophysiology of severe skin burns, clinical treatment modalities and current limitations. We will then focus on MSCs and their potential in the burn wound healing both in in vitro and in vivo studies. A specific attention will be paid to the cell preconditioning approach, as a means of improving the MSC efficacy in the treatment of major skin burns. In particular, we will debate how several preconditioning cues would modulate the MSC properties to better match up with the burn pathophysiology in the course of the cell therapy. Finally, we will discuss the clinical interest and feasibility of a MSC-based therapy in comparison to their paracrine derivatives, including microvesicles and conditioned media for the treatment of major skin burn injuries.