Climate change is the most challenging natural calamity of chronic nature that presents intense episodes of heat waves, and events. Effects of heat waves and increasing average temperature on heat-related illnesses (HRIs) demand a review of existing preventive and treatment strategies to direct future research. Heat-related illnesses are presented as minor to severe life-threatening conditions. Despite the understanding of the pathophysiology of HRI, pharmacological interventions are limited. Prevention is the best strategy against HRI. There is a dearth of epidemiological studies that reviewed the effect of pharmacological interventions on mortality, and there remains a need to identify critical key components other than inflammatory modulators, which can be targeted to decrease HRI.