Transition metals are essential for the function for numerous metalloproteins and cofactors in living systems. Their acquisition, transport, and storage are tightly regulated and the homeostasis of redox‐active cations such as iron and copper is especially critical to prevent the damaging effects of oxidative stress. Indeed the dyshomeostasis of metals has been observed in the pathophysiology of several diseases, and multiple metal‐binding compounds are currently under investigation as therapeutic candidates. Herein, we focus on the altered metal metabolisms of malignant cells and on metal‐binding strategies for the design of cancer chemotherapeutics. Iron, copper, and zinc chelators with a variety of binding motifs have been studied for their antiproliferative effects in malignant cells, and several compounds have reached clinical trials. Recent pro‐chelation approaches, in which the chelator is activated under specific conditions, are poised to increase therapeutic indexes and avoid unwanted side effects. As additional information emerges on the roles of metals in cancer biology, the design of metal‐binding drug candidates is evolving to improve their selectivity and efficacy and to consider their effects on the immune cells present in the tumor microenvironment. In addition, extensive studies to develop inhibitors of metalloenzymes relevant to cancer growth have led to several new anticancer therapeutics that coordinate the zinc centers in the active site of the enzymes. As illustrated by the examples collected herein, approaches that target either labile or protein‐bound transition metals have significant potential to produce new therapeutic options for cancer treatment.