Heavy metals in agricultural soils exist in diverse dissolved (free cations and complexed species of positive, neutral, or negative charges), particulate (sorbed, structural, and coprecipitated), and colloidal (micro- and nanometer-sized particles) species. The fate of different heavy metal species is controlled by the master variables: pH (solubility), ionic strength (activity and charge-shielding), and dissolved organic carbon (complexation). In the rhizosphere, chemical speciation controls toxicokinetics (uptake and transport of metals by plants) while toxicodynamics (interaction between the plant and absorbed species) drives the toxicity outcome. Based on the critical review, the authors recommend omics and data mining techniques to link discrete knowledge bases from the speciation dynamics, soil microbiome, and plant transporter/gene expression relevant to homeostasis conditions of modern agriculture. Such efforts could offer a disruptive application tool to improve and sustain plant tolerance, food safety, and environmental quality.