Food safety has occurred as a high-urgency issue for sustainable agricultural production. Heavy metal (HM)/metalloid toxicity in soil and water substantially impacts agricultural productivity, which is beyond heightened by intense anthropogenic activities and innovative agricultural systems, putting food safety and human health at threat. Other than lowering crop production, enhanced HM toxicity also distracts plant's needs and resource stability. Compensating HM toxicity requires a better knowledge of the intricate mechanisms at physiological, biochemical, molecular, cellular, and plant level that may rise in improved crop productivity. Therefore, plants have set up various internal defense mechanisms against the adverse consequences of HMs. Nonetheless, these internal defense mechanisms are insufficient to devastate the HM toxicity. Plants generate numerous secondary messengers to activate cell signaling, activating the several transcriptional responses connected with plant defense. Hence, the recent improvements in omics approaches, for instance, genomics, transcriptomics, proteomics, metabolomics, miRNAomics, and phenomics, have allowed the characterization of molecular regulators interrelated with HM tolerance. This chapter highlights the plant's responses to HM toxicity. Further, multi-omics approaches have been presented to identify the stress-related key plants to enhance tolerance against HM toxicity in crop plants.
