Erythropoietin, the primary regulator of erythropoiesis, is produced by the kidney and levels vary inversely with oxygen availability. Hypoxia-inducible factor-1 (HIF-1), a major transcriptional regulator of several hypoxia-sensitive genes, including erythropoietin, is functionally deactivated by oxygen in a reaction catalyzed by prolyl hydroxylase. Erythropoietin acts by binding to a specific trans-membrane dimeric receptor which has been found in erythroid and non-erythroid cell types. The interaction between erythropoietin and its receptor ultimately leads to conformational change and phosphorylation of the receptor and expression of genes coding for proteins that are anti-apoptotic. Development of erythropoietin stimulating agents is an area of active research. To date, research has focused on activating the erythropoietin receptor, prevention of HIF-1 inactivation, and gene therapy. Even with biologically effective therapies, defining appropriate hemoglobin targets remains challenging. For example, despite decades of clinical trials, target hemoglobin levels in chronic kidney disease remain uncertain, as hemoglobin targets above 13 g/dl have been associated with both benefit (quality of life) and harm (cardiovascular events).