In chronic inflammation, iron deficiency over time causes a developmental clinical condition ranging from non-anemia to evident microcytic and hypochromic anemia. Pathophysiologically, the iron imbalance in chronic inflammation is mediated by the increase in hepcidin. Its dosage, not yet used routinely, represent an important diagnostic parameter in the setting of anemia, particularly in Anemia of Chronic Deficiency or in the Anemia of Chronic Deficiency/Iron Deficiency Anemia combination. Immunologically, B and T lymphocytes for their activation process need iron to proliferate; in infections, the interaction of myeloid cells, T and B cells, results in inflammatory cytokines secretion which modify iron homeostasis. In chronic inflammation, the rational approach to restore the proper iron flow from the cell to the blood, is to treat the underlying disease, at the same time, adequate iron therapy should be considered. The diagnosis, as well as the correct therapeutic approach to anemia of chronic disease are both increasingly a challenge.