- The physiology and metabolism of grapevine in response to water deficit was studied in the two cultivars Shiraz and Cabernet Sauvignon (Cs), which were shown to differ in their hydraulic behavior. Plant physiology combined with profiling of central and secondary metabolism in leaf and phloem sap highlighted varietal differences in the response to water deficit. Cs displayed lower stomata conductance (gs) at the beginning of the experiment and generally maintained higher soil water content throughout the experiment in comparison to Shiraz. Stomatal conductance was negatively correlated to ABA content. Generally, GC-MS- and UPLC-QTOF-MS/MS-based metabolite profiling analyses revealed a larger impact of water deficit on metabolites involved in central metabolism than on compounds of the specialized metabolism. Comparative analysis based on integrating metabolite profiles via correlation-based network analysis demonstrated that Shiraz exhibits considerably larger stress-related alterations in comparison to Cs. Water deficit caused a shift to lower C/N ratios reflected by an increase in amino acids. Pro, Val, Leu, Thr and Trp were the amino acids with the largest increase in abundance between samples from well watered (IR) plants and plants under water deficit (D). Water deficit caused also a reduction of most organic acids and changes in the phenylpropanoid pathway. We suggest that a tightly regulated transpiration via control of stomata, associated to increased ABA levels in the phloem sap under moderate water deficit, can provide Cs with a buffering capacity to metabolic perturbation under progressive water deficit stress. Taken together these lines of evidence suggest that under prolonged water deficit conditions isohydric like behavior is favored.