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As discussed extensively in this volume, anemia occurs with increasing frequency as people age. Curiously, a specific explanation for anemia is less readily apparent for older patients and approximately one-third of those with anemia over 65 years of age meet criteria for “Unexplained Anemia” (UA) as defined by Guralnik (1) and Artz (2). Although, by definition, those with kidney disease have an explanation for anemia and would not be considered to have UA, erythropoietin (EPO) insufficiency independent of overt renal excretory failure may be one component of this disorder. Certainly, other factors, including the coexistence of occult inflammatory disease, age-associated cytokine dysregulation (independent of inflammation) and androgen deficiency are also likely to contribute. In this chapter, EPO insufficiency will be considered in the context of anemia in general, and late-life UA in particular.