Biomagnification, followed by bioaccumulation of heavy metals (HMs) in the ecosystem, has seriously threatened all organisms, including plants. Heavy metals are hazardous to plants at excessive levels as they engage with various essential macromolecules of cells, including DNA and protein, resulting in an abnormal increase of reactive oxygen species (ROS). Due to the toxicity of heavy metals, plants would suffer from severe morphological, metabolic, and physiological abnormalities, including protein breakdown, lipid peroxidation, and chlorosis of the shoot. Plants use a range of defence mechanisms at cellular as well as physiological levels to withstand the stress caused by heavy metals. However, these natural defensive systems cannot combat the extreme stress experienced by HMs. Plants produce a variety of secondary messengers to initiate cell signaling, triggering several transcriptional reactions linked to plant defence. A range of transcription factor (TF) gene families, such as basic leucine zipper domain (bZIP), WRKY, basic helix-loop-helix (bHLH), Cys2-His2 (C2H2), mitogen-activated protein kinase (MAPK), myeloblastosis (MYB), and APETALA2/ethylene-responsive element-binding protein (AP2/EREBP), are essential for the hormone-mediated pathways that regulate stress under HM stress. Heavy metal stress tolerance of plants depends on two proteins, phytochelatins and metallothionein, which chelate the metal ions in the cytoplasm, followed by the removal and destruction of proteins that cannot function in their natural conformations, the restoration of proteins degraded by stress, and the segregation of metals in the vacuoles. Various strategies have been investigated to comprehend the plant defence mechanism when exposed to heavy metals. Nevertheless, analyzing these defence systems will require much more sophisticated molecular techniques. This book chapter discusses the genes and proteins linked to enhancing the plants’ defence mechanism against HM stress.