Calcium serves as a critical messenger in many adaptation and developmental processes. Cellular calcium signals are detected and transmitted by sensor molecules such as calcium-binding proteins. In plants, the calcineurin B-like protein (CBL) family represents a unique group of calcium sensors and plays a key role in decoding calcium transients by specifically interacting with and regulating a family of protein kinases (CIPKs). Several CBL proteins appear to be targeted to the plasma membrane by means of dual lipid modification by myristoylation and S-acylation. In addition, CBL/CIPK complexes have been identified in other cellular localizations, suggesting that this network may confer spatial specificity in Ca2+ signaling. Molecular genetics analyses of loss-of function mutants have implicated several CBL proteins and CIPKs as important components of abiotic stress responses, hormone reactions and ion transport processes. The occurrence of CBL and CIPK proteins appears not to be restricted to the plant kingdom raising the question about the function of these Ca2+ decoding components in non-plant species.