During the last 50 years, our understanding of the role of the gastrointestinal tract as a first-line defense against the development of postburn sepsis has increased dramatically. Starting with the concept of that gut-derived bacteria cause distant injury, investigators have delineated a complex series of physical changes in the barrier of the gastrointestinal tract. Along with an understanding of these physical changes has come an appreciation of the role of the immune system in modulating postburn organ failure. Importantly, recent investigations into the role of mesenteric lymph have fundamentally changed the paradigm of organ failure and have implicated the gut as a cytokine-secreting organ. This article traces the development of key concepts in the study of burn sepsis and their clinical implications.