Abstract. These Ca 2+ -regulated kinases are part of phosphorylation pathway that lead to regulation of ion channels, v-SNARE proteins, nitrate sensing, nodulation, and transcriptional factors for master regulation. Genome sequencing data of wide varieties of plant species along with high-throughput transcriptomic and functional genomic analysis has expedited revealing of multifaceted functions of these kinases in stress-signaling networks. Combining the transcriptomic and posttranscriptional proteomic regulatory mechanisms in CDPKs and CBL-CIPKs reveals an emerging evolutionary model. Subcellular proteomics and varying affi nity for Ca 2+ emerged as a crucial regulatory mechanism for transducing stress signal. Cross talk of isoforms and their interacting partners adds on to the humongous effect on increasing complexities among these signaling cascades. This chapter provides new insight about the colossal advancement in understanding of the regulatory mechanism and functionality involved in Ca 2+ sensing by kinases in light of the information generated by genomic tools.