Based on its pleiotropic effects, erythropoietin can decrease inflammation, oxidative stress, and apoptosis. Erythropoietin provides organ protection for the heart, brain, and kidney in diverse preclinical animal studies, especially models that include ischemia-reperfusion injury and/or inflammation. However, large clinical studies in coronary reperfusion, heart failure, stroke, acute kidney injury, and chronic renal disease have failed to demonstrate improved outcomes. A study in a previous issue of Critical Care examining the ability of erythropoietin to prevent or ameliorate acute kidney injury in patients undergoing complex valvular heart surgery is similarly negative. The failure of erythropoietin in clinical studies may be due to an inadequate dose, since the receptors responsible for organ protection may require higher concentrations than those responsible for erythropoiesis. However, as has occurred in studies in sepsis and acute respiratory distress syndrome, the negative studies probably reflect an inadequate understanding of the complexity of the underlying processes with multiple redundant and interacting pathways that may differ among the large number of different cell types involved. As tools to understand this complexity and integrate it on an organismal basis continue to evolve, we will develop the ability to use erythropoietin and related nonhematopoietic agents for organ protection.