Oxidative stress caused by reactive oxygen species and, in particular, to hydrogen peroxide (H2O2) has a major impact on all biological systems, including plants and microorganisms. We investigated the H2O2-inducible expression of genes in the cyanobacterium Synechocystis sp. PCC 6803 using genome-wide DNA microarrays. Our systematic screening of a library of mutant lines with defects in histidine kinases (Hiks) by RNA slot-blot hybridization and DNA-microarray analysis suggested that four Hiks, namely, Hik33, Hik34, Hik16 and Hik41, are involved in the perception and transduction of H2O2 signals that regulate the gene expression of 26 of the 77 H2O2-inducible genes with induction factors higher than 4.0. Among the four Hiks, Hik33 was the main contributor and was responsible for 22 of the 26 H2O2-inducible genes under the control of the Hiks. By contrast to Hik33, PerR encoding putative peroxide-sensing protein is involved in the regulation of only nine H2O2-inducible genes.