Drought stress is the main limiting factor for global soybean growth and production. Genetic improvement for water and nutrient uptake efficiency is critical to advance tolerance and enable more sustainable and resilient production, underpinning yield growth. The identification of quantitative traits and genes related to water and nutrient uptake will enhance our understanding of the mechanisms of drought tolerance in soybean. This review summarizes drought stress in the context of the physiological traits that enable effective acclimation, with a particular focus on roots. Genes controlling root system architecture play an important role in water and nutrient availability, and therefore important targets for breeding strategies to improve drought tolerance. This review highlights the candidate genes that have been identified as regulators of important root traits and responses to water stress. Progress in our understanding of the function of particular genes, including GmACX1, GmMS and GmPEPCK are discussed in the context of developing a system-based platform for genetic improvement of drought tolerance in soybean.