Hydrogen peroxide (H2O2) is the most predominant ROS produced during photorespiration and is able to trigger extensive transcriptional reprogramming necessary for subsequent defense responses. To identify components that sense H2O2, transduce and mediate signaling, we have designed several genetic screens. In these, we identified a subunit of the Mediator complex (transcription initiation), MED8, as a negative regulator of early H2O2-responsive gene expression in Arabidopsis thaliana. T-DNA lines harboring insertion in the N-terminal domain of MED8 were embryo-lethal, suggesting the crucial role of MED8 in development. Interestingly, mutants with deletion of the C-terminal glutamine (Q)-rich domain are viable, and display increased tolerance to oxidative stress associated with hyper-activation of defense signaling pathways. When med8 mutation was introduced into the catalase-deficient (cat2) mutant, the cat2 med8 double mutants displayed increased lesion formation, activation of salicylic acid pathway and the induction of pathogenesis-related gene expression. In a second screen, we have exploited the conditional nature of cat2 to identify secondary mutations that modulate the cell death phenotype. The cat2 screen identified components involved in gene expression such as ELP1 and ELP2 of the Elongator complex (transcription elongation) and enzymes required for recycling of photorespiratory metabolites such as the cytosolic glyoxylate reductase GLYR1. Preliminary data suggest that these mutations suppress the cell death phenotype by down-regulating the salicylic acid pathway. In summary, our work report novel components in H2O2-signaling and -dependent gene expression.