As the precise mechanisms that lead to organ dysfunction and death are largely unknown, current treatment is limited to antibiotics and supportive care, rather than targeting molecular derangements. To optimize outcome from sepsis, novel approaches to improve early recognition, treatment and prediction of treatment response are needed. Risk markers associated with the clinical course in patients with early sepsis, will be exploited in pre-clinical models of sepsis (i.e. cells, mice, fruit flies) to identify novel therapeutic targets to feed drug discovery, with a specific focus on preservation of mitochondrial function, which is considered to be the culprit in the induction of organ failure in sepsis. An effective solution to prevent organ failure during physiological extreme conditions is found in nature: hibernation, which is associated with resistance to metabolic stress and longevity. Despite a profound reduction in blood flow and body temperature, hibernators maintain mitochondrial homeostasis and preclude organ injury. The protective mechanisms of hibernation can in part be mimicked by caloric restriction, modulation of energy sensing pathways (i.e. Sirtuins, AMPK) or augmenting hydrogen sulphide (H2S) levels, which might reveal to be a novel cornerstone to preserve mitochondrial function and thereby cellular homeostasis in the treatment of sepsis.