Ethyl pyruvate (EP) is a simple derivative of the endogenous metabolite, pyruvic acid. Treatment with EP has been shown to improve survival and/or ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, such as severe sepsis, acute respiratory distress syndrome, acute pancreatitis and stroke. EP was originally regarded as simply a way to administer pyruvate anion, whilst avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including EP, have pharmacological effects, such as suppression of inflammation, that are quite distinct from those exerted by pyruvate anion. EP has been tested in human volunteers and shown to be safe at clinically relevant doses. It remains to be determined whether EP can be used successfully to treat human diseases.