The perception and subsequent transduction of environmental signals are primary events in the acclimation of living organisms to changes in their environment. Many of the molecular sensors and transducers of environmental stress cannot be identified by traditional and conventional methods. Therefore, the genomic information has been exploited in a systematic approach to this problem, performing systematic mutagenesis of potential sensors and transducers, namely, histidine kinases and response regulators, respectively, in combination with DNA microarray analysis, to examine the genome-wide expression of genes in the unicellular cyanobacterium Synechocystis sp. PCC 6803. Using targeted mutagenesis, 44 out of the 47 histidine kinases and 42 out of the 45 response regulators of this organism have successfully been inactivated. The resultant mutant libraries were screened by genome-wide DNA microarray analysis and by slot-blot hybridization analysis under various stress and non-stress conditions. Histidine kinases have been identified that perceive and transduce signals of low-temperature, hyperosmotic, and salt stress, as well as manganese deficiency.