Almost 80% of dialysis patients have anemia of different severity, with its pathogenesis of multifactorial nature. Relative insufficiency of erythropoietin leading to hyperproliferative erythropoiesis is considered the main underlying cause. Management of anemia has several therapeutic implications, including reasonable quality of life and avoidance of repeated blood transfusions, among others. Optimal maintenance of hemoglobin target levels is not easy, even with the implementation of different therapeutic options, including erythropoietin-stimulating agents (ESAs). Approximately 5–10% of patients are not responding adequately, despite incremental dosing of ESA therapy. That inadequate response has multiple heterogeneous causes, making anemia management rather difficult. Hyporesponsiveness to ESAs is a challenge requiring a proper approach.