Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells endowed with stem-like properties. Importantly, CSCs can survive current standard therapies, resulting in metastatic disease and tumor recurrence. Here we describe the alterations of iron homeostasis occurring in CSCs, which in general are characterized by high intracellular iron content. Importantly, abnormalities of iron metabolism correlate with faster tumor growth and adverse prognosis in cancer patients. In line with the dependence of cancer on iron, we also discuss iron-dependent mechanisms as druggable pathways, as iron chelators have been considered for tumor therapy and new molecules currently proposed and studied as antineoplastic drugs may impinge on iron and its capacity to promote oxidative stress to have therapeutic value in cancer.