Genome editing provides unprecedented opportunities for crop improvement with accelerated speed. However, to realize the full potential of genome editing technologies, identification of the most relevant genes/molecular signatures is very important. The knowledge-driven implementation of genome editing offers a unique opportunity to engineer crop plants more efficiently for genetic enhancement. Several high-throughput genomics approaches are available to discover the molecular signatures associated with important agronomic traits. I shall present a few examples of integrated multi-omics approaches employed by our group to dissect the molecular basis and identify the key candidate genes involved in important agronomic traits. A comprehensive analysis of transcriptome dynamics during seed development in two chickpea cultivars with contrasting seed sizes revealed the candidate genes involved in cell division and endoreduplication processes that determine seed size. Further, an integrated analysis of global transcriptome, proteome, and metabolome profiles of a drought-sensitive and a drought-tolerant rice cultivar under control and drought-stress conditions revealed the preference for auxiliary carbohydrate metabolism through glycolysis and pentose phosphate pathway contributing to drought tolerance. In addition, we demonstrated the role of a candidate homeobox transcription factor in drought stress response. Our studies discovered superior candidate genes/alleles, which can be used as the most promising targets to engineer agronomic traits via genome editing for crop improvement.