<p>Plants are the basis of ecology and biodiversity. Plant resources are of paramount importance to humanity. The development of human civilisations has introduced anthropogenic factors that aggravate abiotic and biotic stress effects. Some advanced techniques, such as molecular tools and omics, can provide a comprehensive understanding of the underlying mechanisms of stress tolerance and provide effective tools for artificial adaptation. External negative signals stimulate intracellular calcium fluctuations. Ca²⁺ messengers, such as calcium-dependent protein kinases (CDPKs or CPKs), trigger MAP kinase phosphorylation cascades regulated by certain stress hormones and are triggered by biotic (ET, JA, and SA) and abiotic (ABA) stresses. In addition to activating regulatory mechanisms, CDPKs exert independent effects on transcription factors and enzymes by bypassing the direct pathway. In this review, we focused on the role of CDPKs in the plant defense system and the promise of their use as activators of the defense system. To fully evaluate the promise of CDPKs, we conducted a (1) detailed analysis of their role in the plant defense system, (2) analysis of their responsiveness to stress, (3) analysis of their overexpression effects, and (4) analysis of intradomain modifications. An in-depth analysis of the available information revealed that CDPKs play a pivotal role in the regulation of plant defense; the expression of certain isoforms is stress-specific and essential for resistance. We suggest that intradomain modifications may be effective tools for increasing plant stress tolerance.</p>