Whereas genetic mutations can alter cell properties, nongenetic mechanisms can drive rapid and reversible adaptations to changes in their physical environment, a phenomenon termed u2018cell-state transitionu2019. Metals, in particular copper and iron, have been shown to be rate-limiting catalysts of cell-state transitions controlling key chemical reactions in mitochondria and the cell nucleus, which govern metabolic and epigenetic changes underlying the acquisition of distinct cell phenotypes. Acquisition of a distinct cell identity, independently of genetic alterations, is an underlying phenomenon of various biological processes, including development, inflammation, erythropoiesis, aging, and cancer. Here, mechanisms that have been uncovered related to the role of these metals in the regulation of cell plasticity are described, illustrating how copper and iron can be exploited for therapeutic intervention.