The chief concerns surrounding the current therapeutic approach to treatment of anemia of CKD are the increased risk of cardiovascular morbidity and mortality when treating to a higher (physiological) hemoglobin target with ESAs, the risk of increased morbidity and mortality with aggressive use of iron repletion, and the management of patients with ESA hyporesponsiveness/resistance or who develop anti-EPO antibodies. The gene discussed is EPO; the disease is anemia (phenotype).