Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.