Heat-related illness (HRI) is a broad term that includes clinical conditions ranging from heat cramps and syncope to heat exhaustion and heatstroke, which may result in death. HRIs are one of the major causes of death worldwide and continue to increase in severity with the rise in global temperature. The identification and estimation of heat-related morbidity and mortality is a major challenge. Heat stress manifests itself into respiratory, cardiovascular, and cerebrovascular disorders, leading to the attribution of the deaths caused by heat stress to these disorders. Although HRIs affect mankind in general, certain occupational workers such as soldiers and athletes are more prone. Various pharmacological and nonpharmacological strategies have been employed to combat HRIs. Despite this, heat exposure results in significant morbidity and mortality. Hence, complete understanding of HRIs at physiological as well as molecular level is required to facilitate design of more efficient preventive and treatment strategies. The impact of heat on mankind is not just restricted to HRIs. Heat treatment, i.e., thermotherapy, has been used extensively since ancient times for relieving pain, making heat a two-edged sword. This review attempts to summarize various HRIs, their physiological and molecular basis, and the state-of-the-art techniques/research initiatives to combat the same. It also illustrates the application of thermotherapy as a means for improving quality of life and morbidity associated with several disease conditions such as fibromyalgia syndrome, heart diseases, cancer, chronic pain, and depression.