The increasing prevalence of multiple comorbidities among anemic patients with chronic kidney disease has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency. Because serum ferritin is an acute-phase reactant and because the inflammatory state may inhibit the mobilization of iron from reticuloendothelial stores, the scenario of patients with serum ferritin >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency, has become more common. This article revisits the basis for the Kidney Disease Outcomes Quality Initiative recommendations regarding the use of serum ferritin and transferrin saturation in guiding iron therapy, then explores some of the newer alternative markers for iron status that may be useful when serum ferritin and transferrin saturation are insufficient. These newer tests include reticulocyte hemoglobin content, percentage of hypochromic red cells, and soluble transferrin receptor, all of which have shown some promise in limited studies. Finally, the role of hepcidin, a hepatic polypeptide, in the pathophysiology of iron mobilization is reviewed briefly.