Technical Abstract: Certain phenolic compounds with antioxidant properties inhibit aflatoxin biosynthesis in the fungus Aspergillus flavus, without affecting growth. Similarly, some of the same phenolics also inhibit biosynthesis of ochratoxin by A. alliaceous. Exposing A. flavus to oxidative stress, such as hydrogen peroxide, enhances aflatoxin biosynthesis. Bioassays with gene-deletion mutants of Saccharomyces cerevisiae, as a model fungus, showed phenolics and reactive oxygen species modulated the antioxidative stress-response system. Caffeic acid was selected as a chemogenomic tool to monitor expression profiling using A. flavus microarrays. These profiles showed that treatment of the fungus with caffeic acid resulted in significant down-regulation of almost all genes in the aflatoxin biosynthetic gene cluster. However, there was little change in expression by laeA and aflR, known regulatory genes of aflatoxin synthesis. Alternatively, a number of peroxiredoxin genes most closely related to alkyl hydroperoxide reductases are dramatically up-regulated by the caffeic acid treatment. These enzymes are believed to reduce amounts of lipoperoxides. The lowering of such peroxides may reduce up-stream signaling from oxidative stress-response pathways that trigger aflatoxin biosynthesis. These results show antioxidative stress response genes are pivotal to modulating expression of the aflatoxin biosynthetic gene cluster.