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Despite several decades of focused investigation, sepsis remains a major cause of mortality in critically ill patients. Advancements in intensive care have enabled more patients to survive the acute phase of sepsis than previously, but a growing number of them progress to chronic critical illness. The failure of previous randomized clinical trials of anti-inflammatory agents to show any pro-survival benefit in septic patients underscores current thought that simple anti-inflammatory strategies are ineffective because the inhibitory effect of anti-inflammatory agents undermines the immune response to pathogens. New strategies with the dual capability of ameliorating inflammation in organs while stimulating antimicrobial activity are eagerly awaited. On the other hand, the metabolic alterations associated with systemic inflammatory response, including mitochondrial dysfunction and metabolic shift, are closely linked through a nexus of signaling pathways and signaling molecules. Preventing these metabolic derangements may be an alternative way to control excessive inflammation, an intriguing possibility that has not been fully explored. New insight into the molecular pathogenesis of sepsis and sepsis-associated chronic critical illness has led to the recognition of septic cachexia, a life-threatening form of metabolic inflammatory complex associated with multiple organ dysfunction. The potential for septic cachexia to serve as a novel target disease state to improve the clinical outcome of septic patients is discussed in this review.