Water Use Efficiency (WUE) is the variable linking assimilation and storage of carbon in plants with the release of water through transpiration. In this study, we combine multiple datasets including global scale leaf-level gas exchange measurements, tree-ring isotopes, flux-tower observations, and remote sensing products with mechanistic terrestrial biosphere modeling to evaluate whether WUE depends on precipitation or aridity levels and how changes in vapor pressure deficit affect ecosystem scale WUE and intrinsic water use efficiency (IWUE). A constrained range of WUE values across ecosystems and climates are observed with few noticeable exceptions. Observations and model simulations converge towards a weak WUE dependency on precipitation or aridity conditions. Numerical simulations with a mechanistic model reveal two distinct signatures of VPD on site level WUE and IWUE, with high VPD resulting in increased IWUE, but decreased WUE. Relations with soil moisture are instead more complex and non-monotonic. Multiple data sources in combination with mechanistic modeling offer new insights on WUE variability across spatial and temporal scales and provide reference WUE values for future comparisons.