Iron hypothesis has been a controversial subject for over 30 years as many studies support its role as a risk factor for cardiovascular disease, while other studies found no evidence to support it. The conflicting results are accounted for by the non-homogeneity of trial design in terms of population inclusion criteria and different endpoints, non-uniform use of parameters for assessing iron role, and incomplete understanding of the mechanisms of action. The nature of iron is dual, being of crucial importance for the human body, but also toxic as "free iron" induces oxidative stress. Under physiological conditions, there are efficient and complex mechanisms against iron-induced oxidative stress, which could be reproduced for creating new, intelligent antioxidants. Iron depletion improves the cardiovascular prognosis only if serum concentration is at the lowest limit of normal ranges. However, low iron levels and the type of dietary iron intake correlate with atherosclerotic cardiovascular disease, influence the ischemic endpoints in the elderly, and exert negative impact on heart failure prognosis. So far, the causal relation and involved mechanisms are not fully elucidated. Iron overload is a difficult and frequent condition, involving the cardiovascular system by specific pathogenic pathways, therefore determining a particular form of restrictive cardiomyopathy and vaso-occlusive arterial damage.