Growing evidence suggests that mitochondrial inhibition plays a major role in the development of multiple organ failure during sepsis. Early correction of tissue hypoxia, strict control of glycaemia and modulation of oxidative and nitrosative stress may protect mitochondria during the acute inflammatory response. Once mitochondrial dysfunction has developed, the regulated induction of a hypometabolic state, analogous to hibernation, may protect the cells from severe bioenergetic failure and a critical fall in ATP. Though this is clinically manifest as organ dysfunction, it may actually represent an adaptive response to a prolonged, severe inflammatory stress. Repair of damaged organelles, stimulation of mitochondrial biogenesis and re-activation of cellular metabolism may accelerate the recovery phase and thus improve clinical outcomes. The aim of this review is to discuss putative interventions aimed at preventing or reversing mitochondrial dysfunction that may have possible clinical relevance, and to stress the importance of the correct timing of intervention.