Ferroptosis and cuproptosis, two recently identified forms of non-apoptotic cell death, have significant relevance in cancer biology due to their higher demand for metal ions. Iron (Fe) and copper (Cu), as transition metals, are critical in cell proliferation, mitochondrial respiration, distant metastases, oxidative stress, and antioxidant defense, all contributing to the onset and advancement of cancer. Given the intertwined relationship of copper and iron in cancer biology, initially studied as independent phenomena, recent evidence suggests a linkage between ferroptosis and cuproptosis. Studies have shown a connection between copper accumulation in mitochondria and the process of ferroptosis. Co-targeting ferroptosis and cuproptosis can be a novel strategy to address refractory cancers by aiming at the vulnerabilities of cancer stem cells and drug-tolerant cells. A potential strategy involves the combination of sorafenib and elesclomol-Cu to target ferroptosis and cuproptosis at the same time. The combined application of iron chelators and copper-lowering agents with chemotherapeutic agents, immunotherapies, radiotherapies, and neoadjuvant therapies holds promise in enhancing antitumor effects across various malignancies. In this chapter, we explore the interconnection between ferroptosis and cuproptosis, elucidate their underlying mechanisms, and discuss their potential as druggable targets in both cancer research and clinical settings.