Iron accumulation in the brain is a common feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). The involvement of iron in these diseases spans across proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. While iron is essential for physiological brain function, its accumulation can lead to neurotoxicity and disease pathogenesis. This review examines the complex role of iron in these neurodegenerative diseases, exploring four hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) iron dyshomeostasis and protein accumulation are parallel and converging pathways. In AD, iron accumulation is associated with cognitive decline and tau pathology, particularly in subcortical regions. Iron dysregulation in AD is influenced by glial cells, with microglial involvement in iron accumulation observed in later stages. In PSP, iron deposition is prominent in subcortical regions, particularly the globus pallidus, subthalamic nucleus, and putamen, and is correlated with tau pathology. In PD, iron accumulation is less pronounced in focused nuclei but is correlated with motor symptoms and cognitive impairment in cortical regions. The review highlights the dynamic nature of iron dysregulation in these diseases, suggesting that iron may play a complex role in both promoting and mitigating proteinopathies. Understanding the intricate relationship between iron and protein pathology is crucial for advancing iron chelation therapies and improving patient outcomes.Iron accumulation in the brain is a common feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). The involvement of iron in these diseases spans across proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. While iron is essential for physiological brain function, its accumulation can lead to neurotoxicity and disease pathogenesis. This review examines the complex role of iron in these neurodegenerative diseases, exploring four hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) iron dyshomeostasis and protein accumulation are parallel and converging pathways. In AD, iron accumulation is associated with cognitive decline and tau pathology, particularly in subcortical regions. Iron dysregulation in AD is influenced by glial cells, with microglial involvement in iron accumulation observed in later stages. In PSP, iron deposition is prominent in subcortical regions, particularly the globus pallidus, subthalamic nucleus, and putamen, and is correlated with tau pathology. In PD, iron accumulation is less pronounced in focused nuclei but is correlated with motor symptoms and cognitive impairment in cortical regions. The review highlights the dynamic nature of iron dysregulation in these diseases, suggesting that iron may play a complex role in both promoting and mitigating proteinopathies. Understanding the intricate relationship between iron and protein pathology is crucial for advancing iron chelation therapies and improving patient outcomes.