Hemoglobin levels in individuals with chronic kidney disease fluctuate frequently above or below the recommended target levels within short periods of time even though the calculated mean hemoglobin remains within the target range of 11 to 12 g/dl. Both pharmacologic features and dosing of erythropoiesis-stimulating agents may lead to cyclic pattern of hemoglobin levels within the recommended range. Several longitudinal studies highlight the complexity of maintaining stable hemoglobin levels over time. As a consequence, patients may risk increased hospitalization and mortality, because both low and high hemoglobin levels are associated with increased cardiovascular events and death. The duration of time that hemoglobin remains higher or lower than the target thresholds may be important to adverse outcomes. It is not clear whether adverse effects of hemoglobin variability are because of the therapy with erythropoiesis-stimulating agents and/or iron or despite such a therapy. Several factors affect hemoglobin variability, including those that are drug related, such as pharmacokinetic parameters, patient-related differences in demographic characteristics, and factors affecting clinical status, as well as clinical practice guidelines, treatment protocols, and reimbursement policies. Strategies that consider each of these factors and reduce hemoglobin variability may be associated with improved clinical outcomes.