Iron is the most abundant transition metal on Earth and essential for life. Iron availability in primordial oceans allowed for its incorporation in living organisms. Metabolic processes catalysed by iron or by iron-sulfur clusters that could be generated in prebiotic settings may be among the first of such processes to evolve on Earth and essential for the emergence of carbon-based life (Bonfio et al., 2017, Varma et al., 2018). The photolysis of water by the process of photosynthesis around 2.45 billion years ago introduced a new global poison i.e. oxygen, causing what is described as the Great Oxygenation Event (Sessions et al., 2009). The resultant oxidising environment transformed iron into a limiting factor for life processes due to the limited solubility of the oxidised iron cation. The ability of iron to cycle through its oxidation states and form coordination bonds is utilised by many enzymes to carry out their catalytic function. Iron has thus emerged as an indispensable cofactor for proteins involved in essential (respiration, DNA replication, cell division) and specialised (oxygen transport, neurotransmission) cellular functions. Iron can serve as a potent oxidant that can wreak havoc on biomolecules, ironically endangering the life that it helps facilitate. This conundrum necessitated the evolution of homeostatic mechanisms to ensure the availability of this critical element while mitigating potential oxidative damage. In the body iron levels are maintained through the precise uptake of iron from the diet. However, the body has no specific physiological mechanism for iron excretion. Iron thus tends to accumulate in certain tissues with age. The brain is a major organ where iron accumulates with age, especially in regions of pathological relevance. The study of monogenic genetic disorders that affect iron homeostasis, and indications from dietary studies, have established that brain iron homeostasis is mostly independent of systemic iron homeostasis (Belaidi and Bush, 2016). Furthermore, indicators of systemic iron levels are weakly correlated with iron in the brain. Several neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD) are associated with increased iron levels in affected region of the brain with levels of iron corresponding to disease severity (Belaidi and Bush, 2016). However, the iron-mediated events that may promote neurodegeneration appear to be more intricate than iron-associated oxidative damage. Here we review the development of the “iron4 hypothesis” of neurodegeneration, shifting our focus beyond iron toxicity to consider the recently (re)discovered iron-dependent programmed cell death pathway called ferroptosis.