The aim of the present review is to highlight the possibilities of a sustainable crop production in the arid Mediterranean region, which is predicted to suffer from increasingly severe droughts in the future due to climate changes, in addition to increased problems with soil salinity and increased temperatures. Annual rainfall in the region varies between 300 and 1000 mm, covering arid, semi-arid and wet ecosystems. As stress factors often act together, it is important sometimes to focus on multiple stresses affecting the crop, instead of looking at the individual stress separated from the rest. The rainfed farming systems are the most important in the Mediterranean countries. The question is if we can overcome mild to medium level of abiotic stresses by agronomic means. It might be done by using different crops of increased drought and salinity tolerance, and utilizing their stress adaptation mechanisms to optimize crop productivity. However supplemental irrigation used as deficit irrigation has the potential to overcome periods of low rainfall or high temperatures. It is suggested that improvements in crop production may arise from several strategies such as early sowing enabled by minimum tillage, increased use of organic manure, and an efficient weed control. Further, crop rotations will play an important role in improving weed control, minimizing disease risk, and increasing nitrogen availability. Introduction of drought and salt tolerant crop species as quinoa, amaranth and Andean lupin may result in more resilient crop rotations and high value cash crop products. Genotypic increases may arise from selection for early vigour, deep roots, increased transpiration efficiency, improved disease resistance, and high assimilate storage and remobilization. A range of crop and management strategies might be combined for a specific target environment in order to optimize crop productivity. These combinations can then be used as a guidance to future decision support systems for crop production at limited water supply under arid Mediterranean conditions.