In 1986, two landmark papers highlighted the discovery of two-component regulatory systems (TCS) in bacteria, marking a significant advancement in understanding bacterial signal transduction. These systems consist of a sensor kinase and a response regulator, with the sensor kinase detecting environmental signals and phosphorylating itself, then transferring the phosphoryl group to the response regulator, which then initiates a cellular response. This system was recognized as a major breakthrough, especially since protein phosphorylation was not yet known to be widespread in prokaryotes. The review highlights the current state of knowledge on TCS, emphasizing their conserved features and the diversity of systems identified through genome sequencing. Despite extensive knowledge, predicting the function of uninvestigated systems remains challenging due to the complexity of factors influencing their behavior. The collection of reviews covers various aspects of TCS, including sensor kinases, response regulators, phosphatases, and network dynamics. It also discusses the biological significance of TCS in all three domains of life and their potential as targets for new drugs. The reviews also address the importance of TCS in microbial pathogenesis and their role in symbiotic relationships. The final section discusses methods for studying TCS, noting that technological advancements have greatly enhanced our understanding of these systems. The authors acknowledge the contributions of the review authors and emphasize the vitality and rapid progress in current research on TCS. The review concludes with a call for continued exploration of TCS, highlighting their significance in microbial biology and potential applications in synthetic biology.In 1986, two landmark papers highlighted the discovery of two-component regulatory systems (TCS) in bacteria, marking a significant advancement in understanding bacterial signal transduction. These systems consist of a sensor kinase and a response regulator, with the sensor kinase detecting environmental signals and phosphorylating itself, then transferring the phosphoryl group to the response regulator, which then initiates a cellular response. This system was recognized as a major breakthrough, especially since protein phosphorylation was not yet known to be widespread in prokaryotes. The review highlights the current state of knowledge on TCS, emphasizing their conserved features and the diversity of systems identified through genome sequencing. Despite extensive knowledge, predicting the function of uninvestigated systems remains challenging due to the complexity of factors influencing their behavior. The collection of reviews covers various aspects of TCS, including sensor kinases, response regulators, phosphatases, and network dynamics. It also discusses the biological significance of TCS in all three domains of life and their potential as targets for new drugs. The reviews also address the importance of TCS in microbial pathogenesis and their role in symbiotic relationships. The final section discusses methods for studying TCS, noting that technological advancements have greatly enhanced our understanding of these systems. The authors acknowledge the contributions of the review authors and emphasize the vitality and rapid progress in current research on TCS. The review concludes with a call for continued exploration of TCS, highlighting their significance in microbial biology and potential applications in synthetic biology.