In patients with chronic kidney disease, erythropoietin resistance is common, costly, and has implications beyond the management of anemia because the presence of erythropoietin resistance portends mortal outcomes. Exploring the provenance of erythropoietin resistance may be facilitated by the consideration of the pathogenetic triad of iron-restricted erythropoiesis, inflammation, and bone marrow suppression. Challenging to diagnose because of difficulty in interpreting tests of iron deficiency, iron-restricted erythropoiesis should be considered in patients who require high doses of erythropoietin, have low transferrin saturation (eg, <20%-25%), and do not have very high ferritin (eg, <1,200 ng/mL); a therapeutic trial of intravenous iron may be worthwhile. Aluminum intoxication is a rare cause of iron-restricted erythropoiesis that may manifest as microcytic hypochromic anemia. A decrease in serum albumin concentration may signal the presence of inflammation, which may be manifest (such as because of a recent illness or infection) or occult; the latter include clotted synthetic angioaccess, failed renal allograft, dialysis catheter, periodontal disease, underlying malignancy, or uremia per se. Marrow hyporesponsiveness may be improved by increasing the delivered dialysis dose, using ultrapure dialysate, maintaining adequate vitamin B12 and folate stores, or by treating hyperparathyroidism. In summary, improving the outcomes of erythropoietin-resistant patients will require complete patient assessment that goes beyond considerations of iron and erythropoietin dose alone. Given that erythropoietin dose is associated with mortality, mitigating erythropoietin resistance has the potential to improve patient outcomes.