Grapevine requires irrigation supply for its cultivation, especially in the arid and semiarid geographic areas. As consequence of the severe climatic changes, water consumption is becoming more and more important as environmental and cost factor that needs to be reduced. Water deficiency can affect berry and wine quality depending on the extent of plant perceived stress, which is a cultivar specific trait. In a four-year project, we tested the physiological and molecular responses to water deficiency of two different table grape cultivars, Italia and Autumn Royal, and we highlighted that they differently adapted to drought stress conditions. Physiological analyses on field-growth plants showed cultivar-specific variations in photosynthetic carbon assimilation and, stomatal conductance under water deficiency. We further combined “omic” analyses to identify candidate genes involved in drought stress response and adaptative traits. Microarray analyses revealed a broad response of cultivar Italia to drought stress conditions characterized by the modulation of 1037 genes involved in biological processes as cell wall organization, carbohydrate metabolism, ROS response, response to hormone and osmotic stress. On the contrary, Autumn Royal response was limited to the modulation of only 29 genes mainly involved in plant stress response, nitrogen metabolism and hormone signal transduction. Our data highlighted that ABA-perception and –signalling are key factors mediating the varietal-specific behavior of the early response to drought.