The brain shares with other organs the need for a constant and readily available supply of iron and has a similar array of proteins available to it for iron transport, storage, and regulation. However, unlike other organs, the brain places demands on iron availability that are regional, cellular, and age sensitive. Failure to meet these demands for iron with an adequate supply in a timely manner can result in persistent neurological and cognitive dysfunction. Consequently, the brain has developed mechanisms to maintain a continuous supply of iron. However, in a number of common neurodegenerative disorders, there appears to be an excess accumulation of iron in the brain that suggests a loss of the homeostatic mechanisms responsible for regulating iron in the brain. These systems are reviewed in this article. As a result of a loss in iron homeostasis, the brain becomes vulnerable to iron-induced oxidative stress. Oxidative stress is a confounding variable in understanding the cell death that may result directly from a specific disease and is a contributing factor to the disease process. The underlying pathogenic event in oxidative stress is cellular iron mismanagement.