Water deficit is associated with multiple abiotic stresses, reducing yields for most crops and leading to economic losses worldwide. A large portion of the world wine production is located in regions suffering - or expected to suffer - from desertification. Whilst grapevine is relatively tolerant to water deficit, extended drought events accompanied by increased temperature can lead to decreased yield, alteration of fruit metabolism and quality. On the other hand, mild environmental stresses are known to increase the synthesis of metabolites (e.g., anthocyanins, stilbenes) in the berries' skin, which can ameliorate fruit quality. In recent years semiarid regions, including the Negev plateau in Israel, are acquiring a significant place in the local wine industry. Moreover, introduction of grapevines in borderline regions between Mediterranean and semiarid climates can provide a model system to investigate current and future scenarios of grape cultivation. Results from these studies can be used to optimize cropping strategies in drought-prone environments, particularly techniques for suboptimal irrigation and the development and testing of drought-tolerant cultivars. In view of the future environmental challenges, this review aims to summarize the current knowledge on physiological and molecular responses of grapevine to multiple stresses associated with water deficit. State-of-the-art irrigation management is also discussed. The need for multidisciplinary integrated studies is suggested as a key-step in elucidating the complex interaction of vine and water deficit.