Manipulation of crop genomics should face the impacts of ongoing population growth and inevitable climate change with consequent increased food needs and further destabilization in accessing arable land and water, leading to aggravated crop losses. Molecular-based tools to optimize plant breeding and develop climate-smart crop cultivars and genotypes are among the most promising approaches to confront such issues. Herein, these tools and emerging devices such as high-throughput sequencing, targeted gene silencing, gene editing, and sophisticated phenotyping are presented. Integrating such biotechnological toolkits with artificial intelligence should be harnessed to boost climate-resilient crop optimization. Also, related processes that supplement smart breeding of plants to upgrade volume and quality of crop yields are highlighted. Such processes as genetic exploration of further wild plant populations, the relevant use of bioinformatics, and exploitation of beneficial multitrophic-plant interactions with intimate settings of pathogens, pests, and their natural enemies should not only boost crop production but also minimize undesirable ecological impacts of climate change. Therefore, the merits of applying improved indices of dispersion of these pests/pathogens for their holistic management rather than inferring their spatial patterns in the climate resilient plant phenotypes are discussed. With the dramatic progress in molecular devices, we need to reveal whole genome data of more key plant species and their wild kins to accelerate their effective adaptation to ecological changes.