Through their pleiotropic actions, statins, fibrates, thiazolidinediones and resveratrol can target multiple mechanisms involved in sepsis. Their actions on mitochondrial function are of interest in a pathological state where bioenergetic failure may play a key role in the development of organ dysfunction. We review these four drug groups as potential adjunctive therapies in sepsis with a particular focus upon mitochondria. Systematic review of clinical and experimental trials was done with a literature search using the PubMed database. Search terms included statins, fibrates, thiazolidinediones, resveratrol, mitochondria, sepsis, peroxisome proliferator-activated receptors, inflammation, oxidative stress and organ dysfunction. With the exception of statins, most of the compelling evidence for the use of these agents in sepsis comes from the experimental literature. The agents all exert anti-inflammatory and anti-oxidant properties, plus protective effects against mitochondrial dysfunction and stimulation of mitochondrial biogenesis. Improved outcomes (organ dysfunction, survival) have been reported in a variety of sepsis models. Notably, positive outcome effects were more commonly seen when the agents were given as pre- rather than post-treatment of sepsis. Statins, fibrates, thiazolidinediones and resveratrol prevent sepsis-induced injury to organs and organelles with outcome improvements. Their effects on mitochondrial function may be integral in offering this protection. Definitive clinical trials are needed to evaluate their utility in septic patients or those at high risk of developing sepsis.