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To cope with environmental stimuli, plants have evolved precise regulatory mechanisms to perceive, transduce and respond to abiotic stresses that can negatively affect growth and development. The CBL-CIPK signaling system is a newly emerging plant-specific and Ca2+-dependent network mediating abiotic stress tolerance. CBLs may sense a Ca2+ signature triggered by abiotic stresses, and have specific interactions with novel CIPK-type kinases after binding Ca2+. The CBL/CIPK complexes may post-translationally phosphory-late downstream target proteins to regulate abiotic stress tolerance in a cell or tissue-specific manner. In some cases transcription factors are induced to activate stress-responsive genes that control adaptation reactions. The CBL-CIPK signaling system exhibits specificity, diversity and complexity. Meanwhile, cross talk also exists in the CBL-CIPK signaling. To date, significant progress has been made in the role of the CBL-CIPK signaling system in responding to salt, low K+ and to high pH, which will provide a fast and efficient method of molecular design breeding combined with the CBL/CIPK engineering of crop plants, for enhanced tolerance to abiotic stresses. How-ever, more CBL/CIPK components remain to be identified, particularly from specific plants that grow in conditions with abiotic stress, and the specificity of their abiotic stress signaling will need to be dissected.