Tolerance to drought is a quantitative trait, with a complex phenotype, often confounded by plant phenology. Breeding for drought tolerance is further complicated since several types of abiotic stress, such as high temperatures, high irradiance, and nutrient toxicities or deficiencies can challenge crop plants simultaneously. Although marker-assisted selection is now widely deployed in wheat, it has not contributed significantly to cultivar improvement for adaptation to low-yielding environments and breeding has relied largely on direct phenotypic selection for improved performance in these difficult environments. The limited success of the physiological and molecular breeding approaches now suggests that a careful rethink is needed of our strategies in order to understand better and breed for drought tolerance. A research programme for increasing drought tolerance of wheat should tackle the problem in a multi-disciplinary approach, considering interaction between multiple stresses and plant phenology, and integrating the physiological dissection of drought-tolerance traits and the genetic and genomics tools, such as quantitative trait loci (QTL), microarrays, and transgenic crops. In this paper, recent advances in the genetics and genomics of drought tolerance in wheat and barley are reviewed and used as a base for revisiting approaches to analyse drought tolerance in wheat. A strategy is then described where a specific environment is targeted and appropriate germplasm adapted to the chosen environment is selected, based on extensive definition of the morpho-physiological and molecular mechanisms of tolerance of the parents. This information was used to create structured populations and develop models for QTL analysis and positional cloning.