Plant breeding has a limited success for developing new cultivars with enhanced adaptation to drought-prone environments, although it has been pursued for various decades. Water use efficiency and water productivity by crops are being sought by agricultural researchers to address water scarcity in drought-prone environments across the world. They may be improved through genetic enhancement. Research on the mechanisms underlying the efficient use of water by crops and water productivity remains essential for succeeding in this endeavor. Advances in genetics, “omics,” precise phenotyping, and physiology coupled with new developments in bioinformatics and phenomics can provide new insights on traits that enhance adaptation to water scarcity. This chapter provides an update on research advances and breeding main grain crops for drought-prone environments.