Forest ecosystems are particularly threatened by global change components, such as increasing frequency and severity of climate extreme events, increasing atmospheric carbon dioxide (CO₂) and pollutants concentrations. All these factors strongly influence the capacity of forests to continue providing important ecosystem services we rely on, including climate regulation and mitigation. On one hand, the increase in atmospheric CO₂ has been shown to significantly affect the coupling between CO₂ assimilation and water loss through transpiration (i.e., water-use efficiency, WUE), though magnitude of changes and main mechanisms involved are still under debate. On the other hand, the human-induced increase in nitrogen emissions — and their deposition back to the biosphere — has enhanced the nitrogen input to forests, which can lead to a cascade of positive (e.g. increasing in tree growth and carbon sequestration in nitrogen limited forests) and negative effects (e.g. shifting the balance between nitrogen retention vs. loss pathways). My talk will provide an overview of the application of stable carbon (δ¹³C), oxygen (δ¹⁸O) and nitrogen (δ¹⁵N) isotope compositions in tree rings and other forest components to get insight into forest WUE and ecosystem nitrogen dynamics in response to global change drivers. Specifically, I will present two case studies, including observations along environmental gradients and what we are learning from a relatively long-term nitrogen manipulation experiment established by our group in Italy.