Significance: Cutaneous wound regeneration is vital to keep skin functions and for large wounds, to maintain human survival. In a deep burn, the ability of the skin to heal is compromised due to the damage of vasculature and resident cells, hindering a coordinated response in the regeneration process. Temporal skin substitutes used as first cover can play a major role in skin regeneration as they allow a rapid wound covering that, in turn, can significantly reduce infection risk, rate of secondary corrective surgeries, and indirectly hospitalization time and costs. Recent Advances: Skin was one of the first tissues to be bioengineered providing thus a skin equivalent; however, what is the current status subsequent to 40 years of tissue engineering? We review the classic paradigms of biological skin substitutes used as first cover and evaluate recent discoveries and clinical approaches adapted for burn injuries cover, with an emphasis on innovative cell-based approaches. Critical Issues: Cell-based first covers offer promising perspectives as they can have an active function in wound healing, such as faster healing minimizing scar formation and prepared wound bed for subsequent grafting. However, cell-based therapies encounter some limitations due to regulatory hurdles, as they are considered as "Advanced Therapy Medicinal Products," which imposes the same industry-destined good manufacturing practices as for pharmaceutical products and biological drug development. Future Directions: Further improvements in clinical outcome can be expected principally with the use of cell-based therapies; however, hospital exemptions are necessary to assure accessibility to the patient and safety without hindering advances in therapies.