The ability of the brain to store a readily bioavailable source of iron is essential for normal neurologic function because both iron deficiency and iron excess in the brain have serious neurologic consequences. The blood-brain barrier presents unique challenges to timely and adequate delivery of iron to the brain. The regional compartmentalization of neurologic function and a myriad of cell types provide additional challenges. Furthermore, iron-dependent events within the central nervous system (CNS) are age dependent (e.g., myelination) or region specific (e.g., dopamine synthesis). Thus the mechanisms for maintaining the delicate balance of CNS iron concentration must be considered on a region-specific and age-specific basis. Confounding factors that influence brain iron acquisition in addition to age-specific and region-specific requirements are dietary factors and disease. This article raises and addresses the novel concept of regional regulation of brain iron uptake by reviewing the developmental patterns of iron accumulation and expression of proteins responsible for maintaining iron homeostasis in a region-specific and cell-specific manner. Understanding these mechanisms is essential for generating insights into diseases such as Hallervorden-Spatz syndrome, in which excess iron accumulation in the brain plays a significant role in the disease process, and should also unveil windows of opportunity for replenishing the brain in a state of iron deficiency.