Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia (MH) are complex syndromes with similar pathophysiology. All three are hypermetabolic states that include high demand for adenosine triphosphate, accelerated oxidative, chemical, and mechanical stress of muscle, and uncontrolled increase in intracellular calcium. Although there are no controlled clinical studies to support a relationship, there is evidence to suggest an association between unexpected heat/exercise intolerance and MH susceptibility. There are multiple case reports and a small number of clinical studies that have used in vitro muscle contracture testing and/or genetic testing to make the association. However, such methodology is problematic in that these tests are validated for clinical MH in association with anesthesia, and not for exertional heat illness or exertional rhabdomyolysis. Nevertheless, these relationships may have implications for some MH-susceptible patients and their capacity to exercise, as well as for clinicians treating and anesthetizing patients with histories of unexplained exertional heat and exercise illnesses.