Heavy metal toxicity is one of the major agricultural concerns that can adversely affect crop growth and yield. Being sessile, plants must evolve a wide array of physio-chemical defense mechanisms to accumulate and tolerate excessive concentrations of heavy metals. These mechanisms, in turn, help in maintaining ionic balance in plant cells, which is physiologically essential for cellular functioning and metabolism. In this chapter, we comprehensively discuss these molecular mechanisms, the signaling responses involved and coordinated cross talk of different processes taking place during heavy metal uptake, translocation, sequestration, and detoxification in plants. Among the key players, recent work has revealed the vital roles played by miRNAs in supplementing metal detoxification by means of transcription factors (TF) or gene regulation. We believe that a complete understanding of the underlying mechanisms may help scientists to adopt novel molecular and genetic approaches that may pave the way for developing transgenic crops with improved heavy metal stress tolerance.