Economically important crops, such as maize, wheat, rice, barley, and other food crops are affected by even small changes in water potential at important growth stages. Developing a comprehensive understanding of host response to drought requires a global view of the complex mechanisms involved. Research on drought tolerance has generally been conducted using discipline-specific approaches. However, plant stress response is complex and interlinked to a point where discipline-specific approaches do not give a complete global analysis of all the interlinked mechanisms. Systems biology perspective is needed to understand genome-scale networks required for building long-lasting drought resistance. Network maps have been constructed by integrating multiple functional genomics data with both model plants, such as Arabidopsis thaliana, Lotus japonicus, and Medicago truncatula, and various food crops, such as rice and soybean. Useful functional genomics data have been obtained from genome-wide comparative transcriptome and proteome analyses of drought responses from different crops. This integrative approach used by many groups has led to identification of commonly regulated signaling pathways and genes following exposure to drought. Combination of functional genomics and systems biology is very useful for comparative analysis of other food crops and has the ability to develop stable food systems worldwide. In addition, studying desiccation tolerance in resurrection plants will unravel how combination of molecular genetic and metabolic processes interacts to produce a resurrection phenotype. Systems biology-based approaches have helped in understanding how these individual factors and mechanisms (biochemical, molecular, and metabolic) "interact" spatially and temporally. Signaling network maps of such interactions are needed that can be used to design better engineering strategies for improving drought tolerance of important crop species.