The systemic inflammatory response observed in the setting of overwhelming infection bears striking similarities to that observed in the setting of severe traumatic injury from a clinical and physiologic standpoint. Recent observations have demonstrated that these disparate clinical entities share common mediators on a molecular level. TLRs, specifically TLR4, and the endogenous molecule high-mobility group box 1 are among the mediators that are known to play a role in inflammation in the setting of sepsis. Evidence is accumulating that demonstrates that these mediators also play a role in the host response to tissue injury. Here, we highlight findings from the 7th World Conference on Trauma, Shock, Inflammation and Sepsis in Munich, Germany, in the context of this growing body of literature.