Iron (Fe) is a ubiquitous redox-active element essential for most life. The formation of localized cell wall appositions, the oxidative burst and the production of pathogenesis-related proteins are hallmarks of plant defense responses. Here, we report that iron is a central mediator linking these three phenomena. We show that in response to pathogen attack, reactive Fe3+, but not Fe2+, is deposited at cell wall appositions where it accumulates and mediates the oxidative burst. We provide evidence that the bulk secretion of Fe3+ provoked by pathogen attack leads to intracellular iron depletion, and that H2O2 itself induces ATP-dependent intracellular iron efflux. Finally, we demonstrate that this intracellular iron depletion promotes the transcription of pathogenesis-related genes in concert with H2O2. This work identifies iron as an underlying factor associated with the oxidative burst and regulating cereal defenses, and establishes links between disease-related iron homeostasis in plants and animals.