Neurodegeneration with brain iron accumulation comprises a clinically and genetically heterogeneous collection of disorders that share key features. These include progressive neurological disease accompanied by high basal ganglia iron and axonal dystrophy. To date, 2 genetic forms have been associated with mutations in PANK2 and PLA2G6, both of which encode proteins that are critical to membrane integrity. The intersection of pathways perturbed by defects in these 2 genes now enables us to test hypotheses of a common pathogenesis and ask why iron accumulates. The mechanisms implicated may contribute to our understanding of more common neurodegenerative disorders with iron dyshomeostasis, including Parkinson and Alzheimer disease.