Prevailing models on the role(s) of inherently reactive cellular metabolites suggest that these molecules are limited to generating non-specific biomolecular damage in cells. Work from our lab and others has shown that the posttranslational modifications formed from these metabolites are more restricted than expected, and that functional modification sites are enriched and conserved within the proteome. This raises a fundamental question: Do intrinsically reactive metabolites and their non-enzymatic modifications on proteins comprise conserved signaling roles in cellular signaling? In this talk I will discuss our recent discovery of a new intracellular communication mechanism integrating glycolysis with the KEAP1-NRF2 pathway through a novel reactive metabolite-induced posttranslational modification. Pharmacologic regulation of this intrinsic feedback loop with a new small molecule inhibitor of central glycolysis enacts cytoprotective cellular responses in NRF2-responsive cellular and in vivomodels of disease. Implications for the role of reactive metabolites, as well as their pharmacologic manipulation, in cellular signaling and disease will be discussed.