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Changing climatic scenario and raising temperature is likely to subject millions of working population across the globe to heat stress at their workplaces. Several epidemiological studies, including our own other studies, stand proof of the adverse effects of heat stress on the health of the workers.  Heat stress imposes a strain on the physiology of workers exposed to heat stress that invokes physiological responses, induces DNA damage and changes in the Heat Shock Protein (HSP) levels in the blood to protect the cells from further damage. We conducted an extensive review and examined published data linking the relationship between occupational heat stress, changes in gene expression and HSPs induced by the DNA damage.  Though the evidence for the mechanistic pathway is limited, the reviewed literature shows strong evidence for the association between occupational heat stress, DNA damage, and HSPs. We conclude that occupational heat stress is a significant risk factor and understanding the association with DNA damage will give key insights in how preventive interventions can be adapted to protect the working population from further adverse effects of occupational heat exposures.