Plants being sessile are susceptible to heavy metals (HMs) toxicity and respond differentially to hostile environments. The toxicity of HM is governed by the type of ion and its concentration, plant physiology and stage of plant growth. Plants counteract the HMs stress by overexpressing numerous stress related proteins, glutathione mediated tolerance pathways and signaling proteins involving networks of various stress regulations. Though the response may vary and be specific in its stress networks regulation for each HM. The intricacy of HM tolerance response involves the set of molecular regulation, which demands to be understood to yield HM tolerant plant. Topical advancements in molecular biology and genomics have facilitated studies in transcriptomics and proteomics to identify regulatory genes implied in HM tolerance in plants. The integration of resources obtained through these studies will be of extreme significance, combining the diverse fields of plant biology to dissect the actual HM stress response network. In this review, we put an endeavor to describe the specific aspects of the molecular mechanisms of a plant response to HMs which may contribute to better understanding of the mode of HMs action and overlaps in metal sensing and signaling/crosstalk to other stresses.