The importance of oxido-reductases in energy metabolism together with the occurrence of various enzymes of central metabolism in the nucleus gave rise to the active research field aiming to understand the moonlighting functions of these enzymes. To take over new tasks, they are post-translationally modified upon upcoming redox-imbalances. Changed properties of the oxidized forms of cytosolic GAPDH, and also of the cytosolic MDH isoforms, and subsequent nuclear translocation, suggest a role as co-activators of gene expression for maintenance of redox-homeostasis. Enzymes of central metabolism have been shown to interact with p53 in mammals or the plant homolog of p53, SOG1 (Suppressor of gamma response 1), a transcription factor involved in the stress response upon UV exposure. Metabolic intermediates, coenzymes or reduced glutathione were shown to fine-tune the various redox-switches, interlinking redox-state, metabolism and induction of new functions via nuclear gene expression. Variations of this basic principle allow for integrating different signals and enable specific responses upon any challenge imposed upon the organism.