Iron is essential for life, but it presents a challenge to our cells because of its ability to drive free radical formation that damages proteins, lipids and DNA. While the consequences of iron excess or deficiency for disease are well described, it has only been recently recognised that iron-induced cell toxicity also forms part of a regulated cell death pathway, termed ferroptosis. This pathway is typically suppressed in tumours, but can be induced by cytotoxic T cells and contribute to anti-tumoural immunity. It is therefore essential to understand how cellular iron levels are controlled. In this thesis, I develop fluorescent iron reporters in cells and use them in genome-wide CRISPR/Cas9 mutagenesis screens, to map the cellular pathways of iron metabolism, identify novel regulators of iron levels, and determine their impact on the induction of ferroptosis. I first generated an iron reporter that is highly sensitive to changes in cellular iron abundance by endogenously tagging Iron Regulatory Protein 2 (IRP2) to the fluorescent protein Clover. I then undertook parallel genome-wide CRISPR/Cas9 mutagenesis screens in HeLa and A549 IRP2-Clover cells to identify genes that when mutagenised disrupt normal iron homeostasis. These screens have allowed me to map the main pathways involved in iron metabolism, as well as uncover genes without known links to iron homeostasis. SETD2, a histone methyltransferase, was a top hit in the screen, and provides the first example of a chromatin modifying enzyme as a mediator of iron levels. SETD2 depletion leads to an increase in the levels of the cargo receptor NCOA4, responsible for selective autophagy of the iron-storing protein ferritin, intracellular iron depletion and activation of the IRP2 response to promote iron uptake. SETD2 loss of function mutations occur in up to 28% of kidney cancers (ccRCCs). I go on to show that SETD2 loss in ccRCCs contributes to resistance to ferroptosis. Therefore, my work not only uncovers an unexpected link between SETD2 function and iron metabolism, but also explains how certain kidney cancers may evade anti-tumoural immunity via their resistance to ferroptosis.