Iron, an essential nutrient for cell proliferation and growth, also has the potential to engage in redox cycling and free radical formation, contributing to both tumor initiation and growth. Recent studies have shown that iron plays a role in the tumor microenvironment and metastasis. Pathways of iron acquisition, efflux, storage, and regulation are perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumor cell survival. Signaling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. The complex relationship between iron and cancer has been facilitated by the recent discovery of new proteins involved in iron metabolism, such as iron efflux pumps, systemic iron regulators, oxidases, reductases, and siderophore-binding proteins. These findings have revealed that proteins involved in iron metabolism can contribute to malignancy in ways that are independent of their primary role in iron metabolism. Clinical and population-based studies have consistently shown that increased levels of iron in the body are associated with increased cancer risk. Intracellular iron regulation is modified in cancer, with cancer cells retaining most elements of the general iron metabolism pathway but differing in the levels or activity of many proteins involved. Cancer cells increase metabolically available iron by increasing iron uptake, decreasing iron storage, and decreasing iron efflux. The ferroportin-hepcidin regulatory axis, which controls iron efflux, is particularly important in cancer. Iron-regulatory proteins, such as IRP1 and IRP2, also play a role in cancer by affecting intracellular iron content. Iron also regulates DNA metabolism and the cell cycle, and affects WNT signaling, which is a key pathway in cancer. Iron chelators, both natural and synthetic, are being explored as potential anticancer therapeutics, and may also be used as chemopreventives. The expression of genes and proteins of iron metabolism could be used to evaluate cancer prognosis and guide therapy. Understanding the specific pathways and proteins targeted by iron depletion is crucial for optimizing therapies.Iron, an essential nutrient for cell proliferation and growth, also has the potential to engage in redox cycling and free radical formation, contributing to both tumor initiation and growth. Recent studies have shown that iron plays a role in the tumor microenvironment and metastasis. Pathways of iron acquisition, efflux, storage, and regulation are perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumor cell survival. Signaling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. The complex relationship between iron and cancer has been facilitated by the recent discovery of new proteins involved in iron metabolism, such as iron efflux pumps, systemic iron regulators, oxidases, reductases, and siderophore-binding proteins. These findings have revealed that proteins involved in iron metabolism can contribute to malignancy in ways that are independent of their primary role in iron metabolism. Clinical and population-based studies have consistently shown that increased levels of iron in the body are associated with increased cancer risk. Intracellular iron regulation is modified in cancer, with cancer cells retaining most elements of the general iron metabolism pathway but differing in the levels or activity of many proteins involved. Cancer cells increase metabolically available iron by increasing iron uptake, decreasing iron storage, and decreasing iron efflux. The ferroportin-hepcidin regulatory axis, which controls iron efflux, is particularly important in cancer. Iron-regulatory proteins, such as IRP1 and IRP2, also play a role in cancer by affecting intracellular iron content. Iron also regulates DNA metabolism and the cell cycle, and affects WNT signaling, which is a key pathway in cancer. Iron chelators, both natural and synthetic, are being explored as potential anticancer therapeutics, and may also be used as chemopreventives. The expression of genes and proteins of iron metabolism could be used to evaluate cancer prognosis and guide therapy. Understanding the specific pathways and proteins targeted by iron depletion is crucial for optimizing therapies.