Drought and heat in dryland agriculture challenge the enhancement of crop productivity and threaten global food security. This review is centered on harnessing genetic variation through biotechnology-led approaches to select for increased productivity and stress tolerance that will enhance crop adaptation in dryland environments. Peer-reviewed literature, mostly from the last decade and involving experiments with at least two seasons' data, form the basis of this review. It begins by highlighting the adverse impact of the increasing intensity and duration of drought and heat stress due to global warming on crop productivity and its impact on food and nutritional security in dryland environments. This is followed by (1) an overview of the physiological and molecular basis of plant adaptation to elevated CO2 (eCO(2)), drought, and heat stress; (2) the critical role of high-throughput phenotyping platforms to study phenomes and genomes to increase breeding efficiency; (3) opportunities to enhance stress tolerance and productivity in food crops (cereals and grain legumes) by deploying biotechnology-led approaches [pyramiding quantitative trait loci (QTL), genomic selection, marker-assisted recurrent selection, epigenetic variation, genome editing, and transgene) and inducing flowering independent of environmental clues to match the length of growing season; (4) opportunities to increase productivity in C-3 crops by harnessing novel variations (genes and network) in crops' (C-3, C-4) germplasm pools associated with increased photosynthesis; and (5) the adoption, impact, risk assessment, and enabling policy environments to scale up the adoption of seed-technology to enhance food and nutritional security. This synthesis of technological innovations and insights in seed-based technology offers crop genetic enhancers further opportunities to increase crop productivity in dryland environments.