Burn trauma in the current age of medical care still portends a 3% to 8% mortality. Of patients who die from their burn injuries, 58% of deaths occur in the first 72 hours after injury, indicating death from the initial burn shock is still a major cause of burn mortality. Significant thermal injury incites an inflammatory response, which distinguishes burns from other trauma. This article focuses on the current understanding of the pathophysiology of burn shock, the inflammatory response, and the direction of research and targeted therapies to improve resuscitation, morbidity, and mortality.