Burn injuries have been devastating and life-threatening throughout history, resulting in physical, psychosocial, and physiological dysfunction in afflicted victims. Our cumulative understanding of burn pathophysiology and therapeutic management has evolved significantly over the past few centuries. Although advancements in surgical techniques, antimicrobial therapy, wound care, and analgesia have improved conventional medical outcomes, burns and ensuing burn-related morbidities (e.g., wounds and hypertrophic scaring) remain prevalent throughout society. Burn-related wounds often present wound healing challenges due to the injury modality, area of involvement, varying depth of penetration, and both local and systemic effects. As both cellular and non-cellular elements constitute the wound microenvironment, understanding their dynamic interactions may help elucidate the temporal and spatial molecular underpinnings that promote skin tissue regeneration instead of fibrotic tissue deposition. A multifaceted approach, utilizing the current gold standard treatments in conjunction with novel cellular and non-cellular therapies, will promote the regeneration of skin structure, function, and aesthetics after tissue injury.