The development of a specific and sensitive immunoassay for the measurement of serum erythropoietin (s-Epo) allows to improve our understanding of the model of in vivo regulation of erythropoiesis. In most anemias, circulating hemoglobin level determines Epo production which in turn stimulates erythropoietic activity. The disruption of the expected feedback mechanism of Epo production leads to an inadequately low s-Epo. The definition of inadequate Epo response to anemia relies on the documentation of a downregulated dependence of s-Epo on Hb with respect to the same dependence in patients with a physiologically regulated erythropoiesis. Literature reports a wide range of so called adequate s-Epo response to anemia and a number of criteria for judging on the adequateness of s-Epo at a certain degree of anemia. The O/P (observed/predicted) ratio allows categorization of each individual patient. The clinical syndromes in which an inadequate Epo response has been reported are numerous and the mechanisms of defective Epo production are different. A number of evidences clearly point to a relation between responsiveness to r-Hu-Epo and inadequate Epo response. This inequivocabily confirms the role inadequate Epo response plays in the pathogenesis of anemia.