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In the perspective of world-wide climate changes that likely will affect the outcomes of plant interactions with pathogens, pests and symbionts, the contribution of a certain class of plant-specific calcium sensors, referred to as calmodulin-like proteins (CMLs), will play an important role in the future. Functional, genetic and bio-technological approaches in the model plant Arabidopsis and, subsequently as a proof of concept, in agricultural important plant species will be necessary to elucidate their function. Several members of CMLs may act as key players in both abiotic and biotic responses including plant/microbe and plant/herbivory interactions. Interestingly, using gain and loss of function strategies, these interactions can be investigated and manipulated by modulating CMLs expression in model plants. It will be important to understand how CMLs translate intracellular calcium signatures generated by various stimuli from pathogenic and beneficial microbes or pests into appropriate biological responses through the regulation of downstream components. The comprehensive analyses of CMLs will first improve our knowledge on Ca2+/CML-mediated signaling pathways but will also facilitate their application in future plant-breeding programs in order to develop highly productive crops.