Sepsis is characterized by an exaggerated inflammatory response, with mobilization of bodily energy reserves to combat the invading microorganism. Despite increasing knowledge on pathophysiology and improved treatment, mortality of sepsis is increasing and calling for new therapeutic strategies. Mitochondria may be a target in reducing organ failure in sepsis, as the severity of mitochondrial dysfunction has been linked to the severity of sepsis. Pre-clinical and clinical data suggest that mitochondrial ‘resuscitation’ is beneficial in sepsis, by improving substrate utilization resulting in an improvement in local energy expenditures. In this review, we will discuss metabolic changes occurring during the course of sepsis and discuss possible strategies that target mitochondria which may be a novel way of reducing organ failure and thereby mortality in sepsis.