Heatstroke is the most severe form of heat-related disorders that include mild heat intolerance, heat exhaustion and heat stress. The incidence of heat-related disorders is increasing due to several factors that include climate change, co-morbidities and drug usage. Patients with heatstroke present with a core body temperature above 408C, multiorgan dysfunction and central nervous system disorder. The pathogenesis of heatstroke is not fully understood; however, heat-shock proteins, inflammatory cytokines and their modulators have been implicated. The clinical biochemistry laboratory plays an important role in the management of patients with heatstroke. Biochemical findings in patients with heatstroke include elevated urea, creatinine, cardiac and skeletal muscle enzymes, myoglobin and troponin. There is also biochemical evidence of metabolic acidosis, respiratory alkalosis, hepatic injury with elevated enzyme levels as well as abnormal hematological and coagulation indices. This review article aims at increasing awareness of the biochemical changes seen in patients with heatstroke and their possible role in prognosis and in elucidating the pathogenesis of heatstroke.