Several lines of evidence indicate that cellular energetics are deranged in sepsis, not by inadequate tissue perfusion but rather by impaired mitochondrial respiration; that is, organ dysfunction in sepsis may result from cytopathic hypoxia. If this concept is correct, the therapeutic implications are enormous. Efforts to improve outcome in septic patients by monitoring and manipulating cardiac output, systemic oxygen (DO2), and regional blood flow are doomed to failure. Instead, the focus should be on developing pharmacologic strategies (e.g., isoform-selective iNOS or PARP inhibitors) to restore normal mitochondrial function and cellular energetics.