Heat stroke (HS), also known as severe sunstroke, is one of the most serious heat-related disorders, characterized by rapid onset, rapid progression, aggressive condition, and high morbidity and mortality. The occurrence and development of HS are closely related to pathophysiological processes such as inflammation, oxidative stress, cell death, and coagulation failure. With the gradual discovery of the pathogenic mechanisms of HS, some drugs or therapeutic approaches targeting its molecular regulatory pathways have shown clinical promise. This review intends to provide an overview of research advances in HS types, pathogenic mechanisms, preclinical and clinically relevant therapeutic strategies, as well as to highlight the potential clinical applications of HS-related biomarkers and therapeutic targets with a view to informing the clinical management of HS.