Sepsis, the principal cause of death in critically ill patients, is associated with impaired oxygen extraction by tissues. One possible explanation is the development of mitochondrial dysfunction and ineffective oxygen utilization. This abnormality has been termed cytopathic hypoxia. This may be caused by an abnormality in the transport of electrons down the cytochrome chain on the mitochondrial inner membrane. In this article we review our studies on abnormalities in the function of complex IV (cytochrome oxidase), the final electron acceptor in this chain. In addition, we provide evidence that administration of cytochrome c may overcome these abnormalities and provide a novel therapeutic alternative.