Our understanding of the broad principles of cellular and systemic iron homeostasis in man are well established with the exception of the brain. Most of the proteins involved in mammalian iron metabolism are present in the brain, although their distribution and precise roles in iron uptake, intracellular metabolism and export are still uncertain, as is the way in which systemic iron is transferred across the blood-brain barrier. We briefly review current concepts concerning the uptake and distribution of iron in the brain, before turning to the ways in which brain iron homeostasis might be regulated. The distribution of iron between different brain regions is then discussed as is the increase in brain iron with normal aging, and the different forms in which iron is present. The increased levels of iron found in specific brain regions and their potential contribution to neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and other polyglutamine expansion diseases, amyotrophic lateral sclerosis, Friedreich’s ataxia, as well as a number of neurodegenerative diseases with iron accumulation, are discussed. The interactions between neuroinflammation and iron are presented, and the chapter concludes with a review of current clinical studies and discussion of the potential and efficacy of iron chelation therapy in the treatment of neurodegenerative diseases.