The interaction of genotype with environment is of primary importance in many aspects of genomic research and is a special priority in the study of major crops grown in a wide range of environments. Water deficit, the major factor limiting plant growth and crop productivity worldwide, is expected to increase with the spread of arid lands. In genetically equivalent cotton populations grown under well-watered and water-limited conditions (the latter is responsible for yield reduction of ∼50% relative to well-watered conditions), productivity and quality were shown to be partly accounted for by different quantitative trait loci (QTLs), indicating that adaptation to both arid and favorable conditions can be combined in the same genotype. QTL mapping was also used to test the association between productivity and quality under water deficit with a suite of traits often found to differ between genotypes adapted to arid versus well-watered conditions. In this study, only reduced plant osmotic potential was clearly implicated in improved cotton productivity under arid conditions. Genomic tools and approaches may expedite breeding of genotypes that respond favorably to specific environments, help test roles of additional physiological factors, and guide the isolation of genes that protect crop performance under arid conditions toward improved adaptation of crops to arid cultivation.