Heavy metal toxicity generally refers to the negative impact on the environment, humans, and other living organisms caused by exposure to heavy metals (HMs). Heavy metal poisoning is the accumulation of HMs in the soft tissues of organisms in a toxic amount. HMs bind to certain cells and prevent organs from functioning. Symptoms of HM poisoning can be life-threatening and not only cause irreversible damage to humans and other organisms; but also significantly reduce agricultural yield. Symptoms and physical examination findings associated with HM poisoning vary depending on the metal accumulated. Many HMs, such as zinc, copper, chromium, iron, and manganese, are present at extremely low levels but are essential for the functioning of plants. However, if these metals accumulate in the plants in sufficient concentrations to cause poisoning, serious damage can occur. Rice is consumed around the world as a staple food and incidents of HM pollution often occur in rice-growing areas. In many rice-producing countries, cadmium (Cd), arsenic (As), and lead (Pb) have been recognized as commonly widespread HMs contaminating rice fields worldwide. In addition to mining and irrigation activities, the use of fertilizers and pesticides has also contributed significantly to HM contamination of rice-growing soils around the world. A number of QTLs associated with HM stress signals from various intermediary molecules have been reported to activate various transcription factors (TFs). Some antioxidant enzymes have been studied which contribute to the scavenging of reactive oxygen species, ultimately leading to stress tolerance in rice. Genome engineering and advanced editing techniques have been successfully applied to rice to improve metal tolerance and reduce HM accumulation in grains. In this review article, recent developments and progress in the molecular science for the induction of HM stress tolerance, including reduced metal uptake, compartmentalized transportation, gene-regulated signaling, and reduced accumulation or diversion of HM particles to plant parts other than grains, are discussed in detail, with particular emphasis on rice.