The metabolic response to trauma and sepsis is characterized by a negative nitrogen balance, accelerated muscle proteolysis, increased ureagenesis, and stimulated acute-phase protein synthesis in liver. Inhibited uptake of amino acids and accelerated protein breakdown in muscle increase the flux of amino acids from the periphery to the liver. Concomitantly, hepatic uptake of amino acids is stimulated and protein synthesis and gluconeogenesis in the liver are enhanced. These events are important to the survival of patients with sepsis. Stimulated ureagenesis resulting in nitrogen loss from the body is another important aspect of hepatic nitrogen metabolism following trauma and sepsis. The mediator(s) initiating metabolic changes is not yet exactly defined, although regulatory protein(s) released from stimulated macrophages (particularly interleukin 1 and tumor necrosis factor) may play a major role in altered amino acid and protein metabolism in muscle and liver during sepsis. However, these factors alone are probably not responsible for the metabolic disturbances, since the catabolic hormones cortisol, glucagon, and the catecholamines can simulate the metabolic pattern observed in sepsis. Other possible mediators include prostaglandins and thyroid hormones. It is possible that the interaction between different types of mediators is necessary for the full manifestation of host responses to severe injury and sepsis.