Research using mammalian burn models has defined significant cardiac deficits after burn injury. The physiologic response to burn and burn complicated by sepsis, including the cardiac dysfunction associated with these insults, remains a very complex physiologic process which, despite active study, remains unclear. The well-characterized inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 continue to play an active role in mediating cardiac dysfunction. However, perhaps of greater interest are the late mediators, high mobility group box 1 and macrophage migration inhibitory factor, because they offer a very realistic window for therapeutic intervention for controlling the inflammatory response. In addition, several other mediators of cardiac dysfunction have been identified and include the heat shock proteins, apoptosis, and the inflammatory caspases. These new mediators provide opportunities for therapeutic intervention, but further research is needed to clarify the importance of their mechanisms of action and the complex interactions between these various signaling pathways.