This thesis presents novel methodologies and discoveries in the study of reactive electrophilic metabolites and electrophilic drugs, using mammalian cells and live zebrafish larvae as models. Chapter 1 details our current understanding and strategies for studying mitochondrial-derived reactive electrophilic metabolites (mt-REMs). Chapter 2 introduces Z-REX, an innovative platform for delivering specific electrophiles to specific proteins in specific tissues of larval zebrafish, enabling the precise study of ligand/drug-target interactions and associated downstream pathways in live animals with high spatiotemporal resolution and minimal off-target effects. Chapter 3 demonstrates that an immunomodulatory electrophilic drug, dimethyl fumarate (DMF, a derivative of the mt-REM fumarate), elicits an innate immune-cell-specific apoptotic program mediated by a novel KEAP1/WDR1 axis, independent of canonical KEAP1/NRF2 signaling.