Marginal lands affected by salinity, water scarcity, nutrient deficiency, and climate extremes represent critical frontiers for addressing global food security challenges. Conventional staple crops often exhibit limited productivity under these abiotic stress conditions, necessitating exploration of novel and underutilized species with intrinsic resilience. This work synthesizes evidence demonstrating how integrated biotechnological approaches, high-resolution genomics, precision molecular breeding, and predictive bio-nano systems, can systematically enhance stress tolerance traits in climate-adaptive crops. High-throughput genomic mapping has identified key regulatory networks conferring drought tolerance, salinity adaptation, and nutrient-use efficiency. For instance, quinoa’s transmembrane protein genes and millet stress-responsive pathways exemplify natural adaptations that can be exploited through genomic-assisted breeding. CRISPR-based genome editing technologies have successfully enhanced abiotic stress tolerance in major cereals by targeting specific genes, such as ZmHDT103 for drought tolerance in maize and TaBAS1 for salt tolerance in wheat. Molecular breeding strategies, including marker-assisted selection and genomic selection, have demonstrated 10–20% improvements in selection efficiency for stress tolerance traits, significantly accelerating genetic gains. Predictive bio-nano systems integrating AI-driven computational models with nanoscale sensors enable real-time monitoring of soil–plant–atmosphere dynamics, facilitating proactive stress management. Empirical evidence confirms that millets, quinoa, halophytes, and orphan legumes exhibit substantial resilience in marginal environments while delivering nutritional, ecological, and economic co-benefits. However, significant challenges persist: regulatory barriers create market access uncertainties for genome-edited varieties, high implementation costs limit adoption by resource-poor farmers, and knowledge gaps remain in translating genomic insights into field-ready cultivars. This integrative framework demonstrates potential to establish resilient agroecosystems on marginal lands, yet successful implementation requires addressing regulatory harmonization, economic accessibility, and bridging the genotype-to-phenotype gap in diverse environmental contexts.