Currently, climate change is threatening farming opportunities to feed a growing population, making necessary the implementation of worldwide cultivable lands, also through the improvement of highly intensified cropping systems such as greenhouses and indoor growing modules. To ameliorate plant performance and reach the potential yield in controlled environment, these systems should be based on the fine control of all microclimatic factors among which vapour pressure deficit (VPD) plays a major role. VPD represents a driver for transpiration in plants, and it is crucial in inducing specific plant structure and physiological behaviour. VPD changes with relative air humidity and temperature, and through its control it is possible to regulate the entire evaporative demand of an indoor cultivation. Therefore, VPD control becomes critical to improve plant growth and productivity. The regulation of VPD in controlled environment should be managed dynamically because VPD can modulate morphophysiological processes in plants, which adapt to the new environmental conditions and in turn, modify the environment itself, thus requiring the continuous update of VPD according to phenological phases. The aim of this review is to report VPD effects on plant growth and physiological processes as carbon metabolism and water use efficiency in controlled environments. Available information about the wide variety of VPD effects on different plant traits and species is summarised, considering the structure-mediated regulation of water fluxes in plant. Towards the goal of optimising cultivation strategies in protected agriculture, the importance of considering possible interaction between VPD and other microclimatic factors is highlighted. Finally, future research areas, which should be explored further, based on needed synergies among different expertise from biological and horticultural fields, are identified and discussed.