Drought triggers a series of physiological and biochemical changes at the stomatal, mesophyll and chloroplast levels, which are linked and integrated into a finely tuned regulatory network that determines plant photosynthetic acclimation and drought tolerance. In this regard, stomatal regulation acts as the primary control, regulating aperture adjustment, density and kinetics, helping to establish the level of carbon dioxide (CO₂) influx in response to hydraulic signals, abscisic acid (ABA) signalling and root-to-shoot chemical messengers. Besides stomata, mesophyll conductance (gm) is considered a decisive factor for CO₂ diffusion influenced by changes in cell wall porosity, membrane permeability, aquaporin (AQP) activity and chloroplast positioning. At the chloroplast level, drought modulates ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activation by dissipating energy through the reorganisation of the thylakoid electron transport, use of alternative electron sinks and non-photochemical quenching (NPQ) to prevent photoinhibition and oxidative damage. The coordinated interplay between these regulatory levels allows plants to adjust their photosynthetic rate (Pn) by dynamically balancing the trade-off between carbon assimilation and water conservation. Gaining insight into this multi-scale integration is critical not only for forecasting plant responses to the escalating drought but also for conceiving the targeted interventions. This article goes a step further in integrating present knowledge on stomatal-mesophyll-chloroplast communication to illustrate how the literature collected can be utilised for breeding and other strategies to enhance water-use efficiency (WUE) and drought resilience in crop systems.