Hemoglobin (Hb) variability is considered a discrete clinical entity that when present may presage poor clinical outcomes. However, Hb variability is an intrinsic property of biological systems and is present in all patients, those with and without the anemia of chronic kidney disease. Taken together, variability actually represents the integration of multiple influences at multiple levels in the life of a red cell, namely the summation of positive and negative influences on erythropoiesis. Thus, Hb variability may be interpreted as a mathematic function of time and is the result of a host of influences including definition of the normal Hb range, native erythron responsiveness/hyporesponsiveness, temporal changes in endogenous and exogenous erythropoiesis-stimulating agent (ESA) levels, the algorithms used to dose ESAs and their duration of action, the presence of biologically available iron, red cell turnover, and recyclable and non-recyclable blood loss and gain. When viewed within this construct of matrixed determinants, the source of hemoglobin variability is more readily identified. When variability is present but the etiology is not easily discerned, erythropoietic hyporesponsiveness must be considered and evaluated. Finally, integration of all of these concepts is possible within the context of an anemia management protocol.