Potentially toxic elements (PTEs) such as cadmium (Cd), lead (Pb), chromium (Cr), and arsenic (As), polluting the environment, pose a significant risk and cause a wide array of adverse changes in plant physiology. Above threshold accumulation of PTEs is alarming which makes them prone to ascend along the food chain, making their environmental prevention a critical intervention. On a global scale, current initiatives to remove the PTEs are costly and might lead to more pollution. An emerging technology that may help in the removal of PTEs is phytoremediation. Compared to traditional methods, phytoremediation is eco-friendly and less expensive. While many studies have reported several plants with high PTEs tolerance, uptake, and then storage capacity in their roots, stem, and leaves. However, the wide application of such a promising strategy still needs to be achieved, partly due to a poor understanding of the molecular mechanism at the proteome level controlling the phytoremediation process to optimize the plant’s performance. The present study aims to discuss the detailed mechanism and proteomic response, which play pivotal roles in the uptake of PTEs from the environment into the plant’s body, then scavenge/detoxify, and finally bioaccumulate the PTEs in different plant organs. In this review, the following aspects are highlighted as: (i) PTE’s stress and phytoremediation strategies adopted by plants and (ii) PTEs induced expressional changes in the plant proteome more specifically with arsenic, cadmium, copper, chromium, mercury, and lead with models describing the metal uptake and plant proteome response. Recently, interest in the comparative proteomics study of plants exposed to PTEs toxicity results in appreciable progress in this area. This article overviews the proteomics approach to elucidate the mechanisms underlying plant’s PTEs tolerance and bioaccumulation for optimized phytoremediation of polluted environments.