Iron is a key micronutrient with a multifaceted role in cell biology, as it is essential for cell survival, cell proliferation, DNA repair, and ATP production. Hence, maintaining a tight control of iron metabolism within cells is imperative. Dysregulation of iron metabolism is tightly associated with all steps of cancer initiation, progression, and metastasis and offers a potential anticancer therapeutic approach. From this perspective, many efforts have been made to deplete intracellular iron stores, either by using iron chelating agents or by interfering with iron metabolism regulatory mechanisms. Nevertheless, it is important to underline that an excessive intracellular iron uptake may lead to an excessive accumulation of intracellular labile iron pool (LIP), which in turn participate to Fenton reactions, thus generating reactive oxygen species (ROS). ROS, on their side, play a double role in cancer biology. When moderate, ROS activate several oncogenic signaling pathways. When ROS production, instead, overwhelms the cellular antioxidant defense, they become harmful or cytotoxic. In this regard, a new form of regulated cell death, known as ferroptosis, caused by the iron-dependent accumulation of ROS was discovered in 2012. From this other perspective, efforts to develop new drugs able to induce ferroptosis (ferroptosis inducers, FINs) have recently provided an alternative antitumor therapeutic strategy. Overall, this chapter is focused on the role of iron metabolism in the modulation of cancer cells and tumor microenvironment (TME) features at different stages of tumorigenesis. Strengths of the current evidence are stressed, knowledge gaps are pinpointed, and controversies surrounding the potential of modulating iron metabolism to develop novel anticancer therapeutic strategy or enhancing the effectiveness of existing drugs are discussed.