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WUEi (intrinsic water use efficiency) is a complex (multi)-trait, that depends on several physiological processes, driving plant productivity and its relation with a changing environment. Climatic change predictions estimate increases in temperature and drought in the semi-arid regions, rendering improved water use efficiency is a mandatory objective to maintain the current global food supply. The aims of this review were (i) to identify through a meta-analysis the leaf traits mostly related to intrinsic water use efficiency (WUEi, the ratio between A net photosynthesis and g(s) - stomatal conductance), based on a newly compiled dataset covering more than 200 species/varieties and 106 genus of C-3 plants (ii) to describe the main potential targets for WUEi improvement via biotechnological manipulations and (iii) to introduce emergent and innovative technologies including UAVs (Unmanned Aerial Vehicles) to scale up levels from leaf to whole plant water status. We confirmed that increases in g(m)/g(s) and V-cmax/g(s) ratios are systematically related with increases in WUEi maintained across species, habitats, and environmental conditions. Other emergent opportunities to improve WUEi are described such as the relationship between photosynthesis and respiration and their link with metabolomics. Finally, we outline our hypothesis that we are observing the advent of a "smart" agriculture, wherein new technologies, such as UAVs equipped with remote sensors will rapidly facilitate an efficient water use regulating the irrigation schedule and determination, under field conditions, of cultivars with improved water use efficiency. We, therefore, conclude that the multi-disciplinary challenge toward WUE has only just begun. (C) 2014 Elsevier Ireland Ltd. All rights reserved.