Water use efficiency (WUE) describes how efficiently plants transpire water to assimilate carbon and produce biomass. Here, we used a variety of data sources, including leaf-level gas exchange measurements, tree-ring isotopes, flux-tower observations, and remote sensing products in combination with mechanistic terrestrial biosphere modeling, to assess how WUE is affected by aridity levels and how it responds to atmospheric (i.e., increase in vapor pressure deficit, VPD) and soil (i.e., decrease in soil moisture) droughts. Observations and model simulations converge towards a very weak WUE spatial dependency on site aridity, which remarks the overall constrained range of average WUE values across ecosystems and climates. Temporally, VPD imparts two distinct signatures on WUE and intrinsic water use efficiency (IWUE), with high VPD resulting in increased IWUE, but decreased WUE. These directional responses can be largely traced back to well-documented leaf-level gas-exchange responses to VPD. Relations of WUE with soil moisture are instead more complex and generally much weaker than the ones with VPD. Multiple data sources in combination with mechanistic modeling offer new insights on WUE spatial and temporal controls and challenge the common assumption that plants in arid and semi-arid climates use water more efficiently.