Increasing evidence implicates a role of iron in the pathogenesis of numerous neurodegenerative diseases due to its capacity to enhance production of toxic reactive radicals and to induce protein aggregation. The underlying mechanism of iron accumulation in areas of the brain specific for the respective disease, however, is still unknown. Recent molecular and biochemical studies provide new insights into the consequences of impairment of brain iron metabolism. This review summarizes our understanding of the regulation of iron in the brain and defines the current knowledge on the involvement of iron metabolism in neurodegenerative diseases with genetically determined iron accumulation in the brain.