Malignant hyperthermia (MH) is a form of heat illness caused by increased heat generation exceeding the body's capacity for heat loss. It is classified separately from other forms of heat illness as the latter require assessment of mental function for differential diagnosis. This is not possible with MH which occurs during general anesthesia when mental function cannot be assessed. MH occurs in genetically predisposed individuals exposed to inhalation anesthetics or succinylcholine. The genetic defects identified so far cause perturbation of skeletal muscle excitation-contraction coupling resulting in myoplasmic calcium dysregulation. The most commonly involved gene is RYR1. Increased myoplasmic calcium leads to hypermetabolism and sustained muscle contractile activity with consequent increased oxygen consumption, carbon dioxide production, sympathetic stimulation, muscle rigidity, heat production, rhabdomyolysis, and disseminated intravascular coagulation. Untreated reactions are fatal. In this chapter we summarize clinical features and management and review current understanding of the pathophysiology and molecular genetics of MH.