• An overview of the leading known copper ionophores is reported. • The application of copper ionophores is discussed in cancer, neurodegeneration, infections, copper deficiency, and diagnosis. • The coordination chemistry and mechanism of action of copper ionophores are discussed. • New strategies to achieve proionophores that can selectively deliver copper to target cells are presented. Copper dyshomeostasis is associated with a plethora of diseases, supporting the possibility of applying copper ionophores to regenerate the metal homeostasis and treat copper-related diseases. Copper ionophores alter the concentration, distribution, and reactivity of endogenous copper ions with consequent profound biological repercussions. The therapeutic use of copper-binding compounds emphasizes the importance of understanding their biological and pharmacological activity. Despite a large number of studies, there is not an adequate and comprehensive view of the coordination chemistry and biological applications of copper ionophores in cancer, microbial diseases, copper deficiency diseases, in neurodegenerative disorders, and the development of PET agents. This article provides an overview of the leading known copper ionophores, focusing on the coordination chemistry, biochemistry, and mechanism of actions of the reported copper ionophores. Recent developments in the field and possible connections, hypotheses, and perspectives in copper ionophore-related research are discussed.