Specific disease resistance of Arabidopsis thaliana against the Hyaloperonospora parasitica isolate Hiks1 (HpHiks1) is mediated by RPP7. Although this disease resistance gene encodes a typical nucleotide binding site leucine-rich repeat (NB-LRR) disease resistance protein, its function is independent of the defense hormone salicylic acid and most known genes required for plant immune responses. We identified EDM2 (enhanced downy mildew 2) in a genetic screen for RPP7 suppressors. Mutations of EDM2 phenocopy RPP7 mutations, but do not affect other tested disease resistance genes. We isolated EDM2 by map-based cloning. The predicted EDM2 protein is structurally unrelated to previously identified components of the plant immune system, bears typical features of transcriptional regulators, including plant homeodomain (PHD)-finger-like domains, and defines a plant-specific protein family. In edm2 mutants both constitutive and HpHiks1-induced RPP7 transcript levels are reduced, suggesting that EDM2 is either a direct or an indirect regulator of RPP7 expression. Microarray analyses defined a set of defense-associated genes, the expression of which is suppressed during successful HpHiks1 colonization of either rpp7 or edm2 plants. This transcriptional phenotype is counteracted by an EDM2/RPP7-dependent mechanism.