Cells can adopt distinct states independently of genetic alterations, a biological process commonly referred to as “cell plasticity”. Acquisition of distinct cell states is characterized by the upregulation of the plasma membrane glycoprotein CD44 in development, immunity and cancer. Although often described as a cell-surface marker, the biological function of CD44 has remained elusive. We discovered that CD44 mediates the uptake of specific metals, including copper and iron in various tissue types using hyaluronans as carriers. This glycan-mediated metal endocytosis mechanism enables immune cell activation and acquisition of a therapy-resistant state of cancer cells. Increase of copper(II) in mitochondria sustains NAD(H) redox cycling, enabling the production of metabolites that co-regulate the epigenetic programming of cell identity. In contrast, increase of iron in the nucleus promotes the activity of specific iron- and ketoglutarate-dependent demethylases, activating specific transcriptional programs. We developed new classes of small molecules that selectively interfere with these metal-catalyzed chemical processes in cells. Inactivating mitochondrial copper(II) prevents acute inflammation in vivo demonstrating that control of cell plasticity confers therapeutic benefits. Activation of lysosomal iron induces ferroptosis in therapy-resistant cancer cells, reducing cancer metastasis. These findings illuminate a universal metal uptake mechanism and the critical role of metals as master regulators of cell plasticity, paving the way towards the development of next generation therapeutics.