Hepatic drug metabolism is altered in critically ill patients. The etiology and mechanisms of the alterations are not clearly understood and are difficult to address in clinical studies. For this reason, in vitro and animal models were developed to investigate the effects of critical illness on hepatic drug metabolism. Specifically, those with sepsis, septic shock, hemorrhagic shock, trauma, neurotrauma, and burns are populations that have been studied. Most of this research, however, has not led to established guidelines for the administration of drugs in these populations.