Iron is a ubiquitous trace element in the human brain that plays an important role in numerous essential biological processes including myelin production, oxygen transport, protein synthesis, mitochondrial respiration, neurotransmitter synthesis, and neurotransmitter metabolism (1,2). Iron mapping across the lifespan therefore provides a window to study metabolism and composition of gray and white matter. While there is no iron in the myelin itself, iron is heavily needed by the oligodendrocytes for myelin synthesis (3). Consequently, iron deficiency in the fetus or during brain maturation may have significant effects on brain development and functioning (4). It is therefore not unexpected that the iron concentration scales with maturation and shows the strongest increase in the first two decades of life (5). Interestingly, iron accumulation shows a highly region specific level and dynamic with highest concentrations found in deep gray matter (5,6). The reason for the accumulation is not clear yet. It was observed that iron in deep gray matter scales with cortical volume which suggest that deep gray matter could be the storage place for metabolic relevant iron (7). On the other hand, iron transport to the brain is considered mainly as a one way traffic which could support accumulation. In the older brain, there is only little increase in iron concentration. Inflammatory and neurodegenerative diseases may further contribute to regional iron accumulation but their effect is rather small compared to ageing effects (8,9).MRI is an attractive tool to non-invasively map the iron content and to learn more about iron accumulation in the human brain because it is particularly sensitive for the iron induced susceptibility changes. However, the relationship between total iron content and resulting susceptibility is complex and typically counteracted by the diamagnetism of the iron containing proteins or carriers and by other tissue component including water (10). The magnetic properties of iron are largely determined by its electrons. Closed subshells have zero magnetic moment, but iron atoms have an unfilled d-shell and therefore a net magnetic moment. The orbital angular momentum of an electron that takes part in bonding is usually quenched while the other electrons still may have a magnetic moment. This moment lines up in an external magnetic field and contributes to paramagnetic behavior which is only slightly opposed by thermal agitation. The thermal agitation tends to produce a random orientation of the magnetic moments and causes a temperature dependent susceptibility (Curie paramagnetism) which shows an inverse proportional relation of susceptibility and temperature. The effective magnetic moment of the electrons can be approximated by the spin-only formula which provides a moment of zero Bohr magnetons (BM) for oxyhemoglobin (spin S=0), a moment of 4.90 BM for iron in deoxyhemoglobin (spin S=4/2), and an effective moment of 3.87 BM for an iron atom in ferritin (spin S=3/2). The resulting (molar) susceptibility is directly proportional to the second power of the effective moment. Among all non-heme iron compounds in the brain, ferritin and hemosiderin are the most relevant candidates. Ferritin is a globular storage protein that keeps iron in a non-toxic and soluble state. In the inner ferritin core with a diameter of about 5-7 mm, up to 4500 iron ions can be stored as hydrated iron oxide (Fe3+) nanocrystal. The nature of this crystal and its magnetic phases is still a matter of debate, but current models consider the surface of the core as paramagnetic and the core as anti-ferromagnetic (under the Neel temperature) with some superparamagnetic behavior (11). For such a model, a linear relationship between total number of iron atoms in the crystal and total susceptibility seems rather unlikely. Hemosiderin is another larger iron compound. In contrast to ferritin, hemosiderin is an amorphous substance with no fixed composition and contains conglomerates of denatured proteins, lipids, and denatured ferritin particles. The iron within hemosiderin was proposed to be Fe3+ oxide or hydroxide and is insoluble, but is in equilibrium with the soluble ferritin pool. Hemosiderin is rarely found in the healthy brain but especially abundant after hemorrhages and can accumulate regionally in pathologies such as hemochromatosis, sickle cell anemia or thalassemia. Other iron compounds in the brain that should be mentioned are hemoglobin (oxygen transport in the blood), transferrin (iron transport), and iron-sulfur proteins. Iron–sulfur proteins are a class of components that assist in vital biochemical tasks in almost every living cell including respiration, iron homeostasis and gene expression. The concentration of transferrin and iron-sulfur proteins is usually below the detection limit of MRI, but their dysregulation can cause regional accumulations of granular iron deposits such as in Friedreich ataxia (12) which are detectable by MRI. From a sub-cellular point of view, most of the iron is intracellular and located in lysosomes and mitochondria. But highest iron concentrations can be found in oligodendrocytes and their processes, in motor neurons, and in myelinated axons. As already mentioned above, myelin itself contains no iron but iron can be found close to the inner shell of the myelin sheets or at the surface where it is associated with the processes of the oligodendrocytes (13)Among the various MRI techniques to assess iron concentration, quantitative susceptibility mapping (QSM) and mapping of the R2* relaxation rate have proven as the most relevant techniques. While they measure different features of iron induced susceptibility changes, they both have shown a linear dependency on iron concentration over the entire physiological range (14,15) and can also be obtained from the same gradient echo sequence. While QSM measures the total bulk susceptibility, R2* mapping is related to the microscopic variation of susceptibility. However, QSM and R2* mapping suffer from the same unresolved problem: The paramagnetism of the iron is counteracted by the diamagnetism of the myelin and its orientational dependency which makes iron mapping in white matter less reliable (16,17).