Abstract: Heavy metal pollution of ecosystems is a global problem. Uptake of heavy metals by plants not only affects the regular growth, but also threatens the health of humans and the whole ecosystem throughout the food chains. Although the analysis of gene expression at the mRNA level has enhanced our understanding of the response of plants to heavy metals, many questions regarding the functional translated portions of plant genomes under metal stress remain unanswered. Acquiring information at the translational and post-translational levels by analyzing and identifying the heavy metal-responsive genes and functional proteins of the plant is needed for a deeper understanding of the response of plants to heavy metal stress. This article analyzes and compares technologies used in studying proteomic responses to heavy metal stress for the past few years and reviews developments in analyzing heavy metal-responsive mechanisms of plants using proteomics. The possibility of illustrating heavy metal detoxification pathways in plants at a sub-cellular proteomic level is discussed. Challenges and strategies encountered in this research field are proposed to provide an effective process in elucidating the molecular mechanism of the interaction between plants and heavy metals.