Heavy metal pollution represents an important environmental problem due to the toxic and nonbiodegradable nature of metals. Physicochemical methods, insofar as available for the removal of metal pollutants from soils and sediments, comprise several inherent disadvantages. Nowadays, removal of metal ions by plants, usually called phytoremediation, has attracted a great deal of attention due to its cost-effective, efficient, and environmental-friendly features. Certain plant species, as compared to the normal plants, encompass the inherent capability to absorb extraordinarily large amounts of metals to their aerial parts. Such plants are useful for phytoextraction-based remediation of heavy metals, and are widely regarded as metal hyperaccumulators. The current advancement of molecular tools has recently improved our understanding regarding the interaction of metals with hyperaccumulators. This chapter comprises the physiological and molecular mechanisms of metal uptake, detoxification, and sequestration by hyperaccumulators. The chapter also examines the recent advances in developing transgenic plants with improved metal accumulation capabilities.