Innate immunity represents the first line of inducible defense against microbial infection in plants and animals 1– 3. In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs), such as flagellin, initiates convergent signalling pathways involving MAP kinase (MAPK) cascades and global transcriptional changes to boost immunity 1– 4. Although Ca 2+ has long been recognized as an essential and conserved primary mediator in plant defense responses, how Ca 2+ signals are sensed and relayed into early MAMP signalling is unknown 5, 6. Here, we use a functional genomic screen and genome-wide gene expression profiling to show that four calcium-dependent protein kinases (CDPKs) are Ca 2+ sensor PKs critical to transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control early genes involved in synthesis of defense peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by flg22, as well as compromised pathogen defense. In contrast to negative roles of calmodulin (CAM) and a CAM-activated transcription factor in plant defense 7, 8, the present study reveals Ca 2+ signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling.