Sepsis is frequently characterized by a number of metabolic abnormalities: increased plasma lactate concentration, metabolic acidosis, increased glycolysis, and an abnormal "delivery-dependent" oxygen consumption. Two hypotheses have been advanced to explain these metabolic abnormalities: (1) cellular hypoxia resulting from abnormal microcirculatory blood flow or (2) defect(s) in energy-producing metabolic pathways of cells. Results of our studies on rat muscle, liver, heart, brain, and plasma suggest that there is no evidence of bioenergetic failure in these septic tissues and that the increase in lactate production is not necessarily due to cellular hypoxia. The adequacy of cellular oxygenation and bioenergetics was verified using in vivo phosphorus 31 nuclear magnetic resonance spectroscopy, [18F]fluoromisonidazole, and microfluorometric enzymatic techniques. Findings from these studies as well as results from several clinical investigations indicate that neither hypothesis can adequately account for the metabolic features typical of sepsis and that the pathophysiology of sepsis awaits further clarification. These studies and important clinical implications are discussed.