The development of systemic inflammation, acute lung injury, and multiple organ failure after a major thermal injury, as well as nonthermal forms of trauma, remain relatively common causes of morbidity and mortality. During the past two decades, increasing recognition that the ischemic gut may contribute to the development of sepsis and organ failure in burn patients, as well as other critically ill patient populations, has led to new hypotheses to explain burn-induced multiple organ failure as well as highlighted the importance of early enteral nutrition. Thus, the goal of this review will be to provide a perspective on the evolution of the gut hypothesis of systemic inflammation and distant organ dysfunction.