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Several pollutants interfere with plant metabolism and heavy metals (HMs) are one of the most common. The HM toxicity can cause plant growth retardation, inhibition of photosynthesis, induction and inhibition of enzymes, DNA damage, and the generation of oxidative stress. To avoid toxicity from HMs, plants developed a range of different response mechanisms acting in additive and/or synergistic ways. The plant protection against metal toxicity occurs through control of root uptake of metal and metal transport within the plant. Proteins such as ferritin, metallothioneins, and glutathione-derived peptides (phytochelatins) and organic molecules such as organic acids and phytate play an important role in plant storage and detoxification process in metal homeostasis; when these systems are overloaded, oxidative stress defense mechanisms are activated. Understanding the functioning of these mechanisms in climate change is of utmost importance to understanding the process of adaptation of plants to environmental changes and their use in bioremediation process. This chapter chapter briefly summarizes some recent aspects of biological, molecular, and proteomic mechanisms concerning the responses of plants to HMs.