Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.