Heat stress (HS) reduces production and efficiency in almost every metric of the dairy operation, and it thus compromises profitability and sustainability. If the magnitude of HS progresses, it can become lethal. Death can occur acutely or days following the heat load, even if environmental conditions have become nonstressful. Consequently, lethal heat stress (LHS) is often difficult to identify and almost always misdiagnosed. The precise mechanisms of death when dairy cows succumb to LHS has not been fully elucidated or documented, but the pathophysiology of LHS appears to be conserved among several species. The unique digestive physiology of ruminants adds additional layers of complexity that contribute to failure of multiple systems involved with LHS. Consequently, the ostensible etiology and pathogenesis of LHS described herein is extended from the physiological adaptations cows use to survive HS and pertinent pathology extrapolated from other species. The multifactorial causes of death likely involve dysfunction and imbalance of several interdependent systems as follows: (1) electrolyte dyshomeostasis, (2) unstable blood pH, (3) gastrointestinal tract hyperpermeability, (4) sepsis, (5) severe immune activationinduced inflammation, (6) disseminated intravascular hypercoagulation, (7) systemic endothelial permeability, (8) multiple organ failure, and (9) circulatory failure. Having a better understanding of the mechanisms of LHS will improve diagnosis, enable a more accurate prognosis, and provide insight into strategies aimed at preventing dairy cow mortality and morbidity.