Multiple lines of evidence support the hypothesis that ischemia-induced impairment of normal gut barrier function, with loss of the normal tonic counterinflammatory influence of the gut immune system, contributes to the expression of uncontrolled inflammation in critically ill victims of trauma and overwhelming infection. The clinical syndrome known as the systemic inflammatory response syndrome (SIRS), which embodies uncontrolled inflammation in trauma and sepsis, is reproduced in its entirety by vigourous exercise, raising the possibility that the gut may also play a role in exercise-induced inflammation. Both strenuous exercise and systemic sepsis result in impairment of the normal gut barrier to luminal microorganisms, and result in elevated circulating levels of bacterial endotoxin. Under normal circumstances, the immune tissues of the gut-liver axis inhibit the expression of a host response to foodstuffs in the gut lumen, or to the indigenous microbial flora of the gut wall. This influence is an active, energy-requiring process. Both strenuous exercise and critical illness are associated with gut ischemia, providing a common biologic basis for the initiation of a dysregulated inflammatory response. Although direct evidence supporting or refuting the hypothesis that the gut can serve as a trigger for systemic inflammation following strenuous exercise is sparse, the similarities in the clinical manifestations of SIRS and exercise, and the promising results of prophylactic or therapeutic gut-directed strategies in critical illness, suggest that similar approaches may provide benefit for individuals engaged in extreme physical exercise.