The role of transferrin in iron delivery to tissues is described. Transferrin-dependent iron uptake by erythroid cells in the bone marrow is essential for the development of erythrocytes, while nontransferrin-bound iron can be taken up in tissues such as liver. On the basis of the evidence that iron distribution in the body is changed by iron saturation of plasma transferrin, the role of transferrin in iron delivery to the brain is reviewed. In the case of transient iron saturation of plasma transferrin, ⁵⁹Fe concentrations in the brain of iron-loaded mice are approximately 40-50% of those of control mice in all brain regions tested except the choroid plexus, in which the ⁵⁹Fe concentration is equal. A similar distribution of ⁵⁹Fe in the brain is also observed in neonatal hypotransferrinemic (HP) mice, which have a splicing defect in the transferrin gene, resulting in < 1% of the normal plasma levels of transferrin. These results suggest that transferrin-bound iron is responsible for the fraction of iron in the circulation that enters the brain. On the other hand, the iron concentration in the brain of HP mice is approximately three times higher than that in nonmutant mice. It is likely that the management of iron is affected in the brain of HP mice. Brain transferrin may be involved in the management of iron in the brain.