Significance: While atherosclerosis is an almost inevitable consequence of aging, food preferences, lack of exercise, and other aspects of the lifestyle in many countries, the identification of new risk factors is of increasing importance to tackle a disease, which has become a major health burden for billions of people. Iron has long been suspected to promote the development of atherosclerosis, but data have been conflicting, and the contribution of iron is still debated controversially.

Recent Advances: Several experimental and clinical studies have been recently published about this longstanding controversial problem, highlighting the critical need to unravel the complexity behind this topic.

Critical Issues: The aim of the current review is to provide an overview of the current knowledge about the proatherosclerotic impact of iron, and discuss the emerging role of non-transferrin-bound iron (NTBI) as driver of vasculotoxicity and atherosclerosis. Finally, I will provide detailed mechanistic insights on the cellular processes and molecular pathways underlying iron-exacerbated atherosclerosis. Overall, this review highlights a complex framework where NTBI acts at multiple levels in atherosclerosis by altering the serum and vascular microenvironment in a proatherogenic and proinflammatory manner, affecting the functionality and survival of vascular cells, promoting foam cell formation and inducing angiogenesis, calcification, and plaque destabilization.

Future Directions: The use of additional iron markers (e.g., NTBI) may help adequately predict predisposition to cardiovascular disease. Clinical studies are needed in the aging population to address the atherogenic role of iron fluctuations within physiological limits and the therapeutic value of iron restriction approaches. Antioxid. Redox Signal. 35, 387–414.