Routine administration of erythropoietin (EPO)-stimulating agents (ESAs) for the control of anemia has improved the quality of life of subjects with chronic kidney disease (CKD). However, a wide variation in individual response to ESA is often observed. The reasons for EPO resistance include demographic variables such as age and gender distribution, morbidity pattern, and modality of dialysis. Despite suggestions by observational data, there is no biological characteristic that puts children at a disadvantage for adequate response to ESA. On the contrary, children possess a superior capacity for red cell production, including extramedullary erythropoiesis. The reasons for larger requirement of ESA in children (than in adults) are greater inflammatory burden, disproportionate blood loss, and greater EPO dosing by pediatric physicians. To minimize the harmful (including fatal) consequences of EPO resistance, surveillance programs must replenish nutrient (for example, iron and folate) stores, minimize oxidative hemolysis, control hyperparathyroidism, avoid catheter infection, and optimize uremic clearance. This clinical approach is justified by the inadequacy of laboratory diagnosis of pertinent etiological factors. Indeed, the best proof for functional nutrient deficiency is often a therapeutic trial. Finally, there are upcoming therapeutic agents that exploit the capacity for an endogenous EPO synthesis in CKD subjects, and may therefore minimize the off-target effect of excess dosages.