The sepsis response to infection includes disturbed metabolism. New insights have allowed a better characterization of the changes in energy expenditure, use of energy substrates, body composition, and muscle protein wasting in sepsis. Energy expenditure is decreased in the early phase of sepsis and increase only at a late stage, implying early macronutrient restriction. The flow of energy substrates is redirected to fuel the endogenous production of glucose, via increased lipolysis and proteolysis. The clinical phenotype of a patient with sepsis is characterized by an increase in extracellular water and decreases in fat and muscle mass. At the subcellular level, the mitochondrial capacity for generating cellular energy is decreased and used for functions necessary for short-term cell survival. Likewise, recent metabolomic studies have demonstrated an accumulation of lactate, pyruvate, metabolites of the tricarboxylic acid (TCA) cycle, altered oxidation of fatty acids, and increased proteolysis. The use of therapies targeting the clinical phenotype while preserving adaptive events can now be envisioned by the bedside application of metabolomic techniques.