Among other environmental instabilities, drought stress is the primary limitation to cereal crops growth, development and productivity. In the context of continuing global climate change, breeding of drought resistant crop cultivars is the most economical, effective and sustainable strategy for adapting the crop production system and ensuring food security for the growing human population. Additionally, there is need for improving management practices. Whereas conventional breeding has sustained crop productivity gains in the past century, modern technological advancements have revolutionized our identification of important drought tolerance genes and underlying mechanisms, and accelerated new cultivar development. Large-scale high throughput sequencing, phenotyping, 'omics' and systems biology, as well as marker assisted and quantitative trait loci mapping based breeding approaches have offered significant insights into crop drought stress tolerance and provided some new tools for crop improvement. Despite this significant progress in elucidating the mechanisms underlying drought tolerance, considerable challenges remain and our understanding of the crop drought tolerance mechanisms is still abstract. In this chapter, therefore, we highlight current progress in the identification of drought tolerance genes and underlying mechanisms, as well as their practical applications. We then offer a holistic approach for cereal crops adaptation to future climate change exacerbated drought stress.