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Species-specific responses of plant intrinsic water-use efficiency (iWUE) to multiple environmental drivers associated with climate change, including soil moisture (theta), vapor pressure deficit (D), and atmospheric CO2 concentration (c(a)), are poorly understood. We assessed how the iWUE and growth of several species of deciduous trees that span a gradient of isohydric to anisohydric water-use strategies respond to key environmental drivers (theta, D and c(a)). iWUE was calculated for individual tree species using leaf-level gas exchange and tree-ring delta C-13 in wood measurements, and for the whole forest using the eddy covariance method. The iWUE of the isohydric species was generally more sensitive to environmental change than the anisohydric species was, and increased significantly with rising D during the periods of water stress. At longer timescales, the influence of c(a) was pronounced for isohydric tulip poplar but not for others. Trees' physiological responses to changing environmental drivers can be interpreted differently depending on the observational scale. Care should be also taken in interpreting observed or modeled trends in iWUE that do not explicitly account for the influence of D.