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Food safety has emerged as a high-urgency matter for sustainable agricultural production. Toxic metal contamination of soil and water significantly affects agricultural productivity, which is further aggravated by extreme anthropogenic activities and modern agricultural practices, leaving food safety and human health at risk. In addition to reducing crop production, increased metals/metalloids toxicity also disturbs plants’ demand and supply equilibrium. Counterbalancing toxic metals/metalloids toxicity demands a better understanding of the complex mechanisms at physiological, biochemical, molecular, cellular, and plant level that may result in increased crop productivity. Consequently, plants have established different internal defense mechanisms to cope with the adverse effects of toxic metals/metalloids. Nevertheless, these internal defense mechanisms are not adequate to overwhelm the metals/metalloids toxicity. Plants produce several secondary messengers to trigger cell signaling, activating the numerous transcriptional responses correlated with plant defense. Therefore, the recent advances in omics approaches such as genomics, transcriptomics, proteomics, metabolomics, ionomics, miRNAomics, and phenomics have enabled the characterization of molecular regulators associated with toxic metal tolerance, which can be deployed for developing toxic metal tolerant plants. This review highlights various response strategies adopted by plants to tolerate toxic metals/metalloids toxicity, including physiological, biochemical, and molecular responses. A seven-(omics)-based design is summarized with scientific clues to reveal the stress …