Environmental pollution of heavy metals (HMs), mainly due to anthropogenic activities, has received growing attention in recent decades. HMs, especially the non-essential carcinogenic ones, including chromium (Cr), cadmium (Cd), mercury (Hg), aluminum (Al), lead (Pb), and arsenic (As), have appeared as the most significant air, water, and soil pollutants, which adversely affect the quantity, quality, and security of plant-based food all over the world. Plants exposed to HMs could experience significant decline in growth and yield. To avoid or tolerate the toxic effects of HMs, plants have developed complicated defense mechanisms, including absorption and accumulation of HMs in cell organelles, immobilization by forming complexes with organic chelates, extraction by using numerous transporters, ion channels, signalling cascades, and transcription elements, among others. OMICS strategies have developed significantly to understand the mechanisms of plant transcriptomics, genomics, proteomics, metabolomics, and ionomics to counter HM-mediated stress stimuli. These strategies have been considered to be reliable and feasible for investigating the roles of genomics (genomes), transcriptomic (coding), mRNA transcripts (non-coding), metabolomics (metabolites), and ionomics (metal ions) to enhance stress resistance or tolerance in plants. The recent developments in the mechanistic understandings of the HMs-plant interaction in terms of their absorption, translocation, and toxicity invasions at the molecular and cellular levels, as well as plants' response and adaptation strategies against these stressors, are summarized in the present review. Transcriptomics, genomics, metabolomics, proteomics, and ionomics for plants against HMs toxicities are reviewed, while challenges and future recommendations are also discussed.