Plants are continuously subjected to multiple abiotic stresses throughout their whole life cycle, including drought, salinity, extreme low/high temperature, and metal toxicity, which severely constrain crop growth, development and yield formation. To adapt to variable adverse environments, plants have evolved sophisticated calcium signal transduction networks that enhance stress adaptability by dynamically regulating the expression of stress-responsive genes. Calmodulin (CaM) and calmodulin-like proteins (CMLs) serve as the core calcium signal decoders in plants. They play central regulatory roles in abiotic stress responses by binding to downstream target proteins and modulating their activities. Stress stimuli trigger specific cytosolic Ca²⁺ signatures; after perceiving these Ca²⁺ signals, CaM/CML proteins interact with diverse transcription factors such as CAMTA, CBP60, Group IId WRKY, MYB, NAC and bZIP. This interaction mediates genome-wide transcriptional reprogramming, further regulating pathways involving antioxidant systems, ion homeostasis and hormone signaling, and ultimately conferring stress tolerance in plants. This review systematically summarizes the structural and functional characteristics of CaM/CML-binding transcription factors, with an emphasis on the molecular mechanisms of CaM/CML-mediated transcriptional regulation in general stress responses, as well as under cold, heat, salt, drought, and metal ion stress conditions. We also summarize the conservation and species-specificity of CaM/CML signaling pathways under different stresses, and dissect the crosstalk regulatory networks between CaM/CML signaling and phytohormone signals including abscisic acid, salicylic acid, and jasmonic acid. In addition, we propose key scientific challenges in this research field, covering the binding specificity of CaM/CML with transcription factors, the function of liquid-liquid phase separation, and the crosstalk response to multiple combined stresses. We further explore the application potential of single-cell sequencing, multi-omics integration and CRISPR/Cas9 gene editing technology in deciphering regulatory networks and improving crop stress resistance. In-depth clarification of CaM/CML-mediated transcriptional regulatory mechanisms can provide a theoretical basis and core gene targets for molecular breeding of stress-tolerant crops, and is of great scientific value and practical significance for breeding climate-smart crops and advancing green sustainable agricultural development.
