Cellular oxygen sensors are not only sensitive to oxygen but also to iron levels. Accordingly, they are ideally positioned to serve important roles not only in oxygen sensing but also in iron homeostasis and dyshomeostasis. Here, I review the literature which supports the notion that iron is essential for neurodegeneration including stroke, Alzheimer’s disease, Parkinson’s disease, and Neurodegenerations with Brain Iron Accumulation via its ability to optimize activities of oxygen-sensing, hypoxia inducible factor (HIF) prolyl hydroxylases. In this context, HIF PHDs act to drive prodeath transcription via the leucine zipper transcription factor ATF4, and not via decreases in HIF stability. I also discuss evidence which suggests that oxidative stress leads to cell death via a programmed pathway of ferroptosis that is unlikely to involve random, non-enzymatic, Fenton-mediated radical formation. Altogether, this evolving model broadens our view of how oxygen sensors and iron can regulate cell degenerations in neurological diseases under normoxic or hypoxic conditions.