Anemia is one of the most common and morbid complications of chronic kidney disease, causing unpleasant symptoms and reducing the quality of life. The availability of recombinant human erythropoietin (rHuEPO) in 1989 has been one of the most important developments in the care of this population in the past several decades. Treatment with erythropoiesis-stimulating agents (ESAs) has improved patients’ lives, but recent studies have found that higher hemoglobin (Hgb) targets cause harm, resulting in more cautious treatment. Despite widespread recognition by clinicians and patients of the value of this biological agent, the high cost and new concerns over safety have led to a reexamination of its use. Although rHuEPO is prescribed by individual physicians and target Hgb is guided by current evidence in the context of individual patients, critics within and outside the medical community have charged that rHuEPO is being overused, that financial motives are driving its use, and that patients are suffering from adverse consequences. Regulatory agencies, including the Centers for Medicare and Medicaid Services and the US Food and Drug Administration, have weighed in as well. In this review article, issues related to the current and future status of ESA treatment will be considered with a view to assessing factors that result in a lack of clarity and need for further study. It is essential that the renal community vigorously support additional rigorous research to expand the evidence base for optimal anemia management so that the debate over appropriate ESA use remains where it belongs, in the scientific domain.