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The clinical process of severe sepsis is characterized by extreme inflammation interlinked with potent stimulation of the coagulation cascade often followed by a state of relative immune paralysis. In this paper, we will review many of the potential therapies directed at various steps along the inflammatory cascade from modulation of inflammatory mediators eliciting the immune response, alteration of the host's immune response in both a stimulatory and depressive manner, and taming the overexuberant coagulation response triggered by the fierce coagulation-inflammation cycle. Finally, we will discuss further opportunities for research to improve our ability to design effective therapies.