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 phosphorylate 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. However, 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.