Malignant hyperthermia (MH) is a pharmacogenetic, life-threatening hypermetabolic syndrome in genetically predisposed individuals exposed to certain anesthetic agents. Discovered by Denborough and Lovell  in 1960, MH was associated with high mortality and morbidity as the cause was unknown and an effective treatment was unavailable. There is no classic clinical presentation of the syndrome, and the onset and signs of MH are dependent upon known and unknown environmental and genetic factors. Initial theories involved central temperature regulation defects or uncoupling of oxidative phosphorylation in mitochondria , but later investigations targeted skeletal muscle as the affected organ. Subsequently freshly biopsied skeletal muscle was used for in vitro pharmacologic contracture testing to discriminate between normal and MH-affected muscle and remains the “gold standard” for MH diagnosis. Spontaneous, genetic models for MH were discovered in pigs and dogs and substantial knowledge about MH was gained from these valuable resources. The abnormal contracture response of MH skeletal muscle evoked a focus on calcium regulation, and abnormalities in calcium release (as opposed to calcium sequestration) mechanisms were discovered. About this same time the major calcium release channel in the skeletal muscle sarcoplasmic reticulum membrane was purified and named the ryanodine receptor . Although the ryanodine receptor represents one of the largest functional proteins, the enormous gene encoding the 5021 amino acids comprising the ryanodine receptor subunit was eventually cloned [4,5]. Patient and dedicated work on the ryanodine receptor gene has found linkage to MH in the pig , dog , and among several different mutations and MH in unrelated human families [8,9]. Expression of these mutations in HEK cells has resulted in abnormal calcium release [10,11], supporting but not proving a causal basis for MH. In this review each of the areas mentioned above is discussed in detail revealing a wonderful success story that changed the anesthesiologists “worst nightmare” from a syndrome with high mortality and morbidity to a reasonably well managed disease today. This success story includes unraveling the molecular basis for the disease and brings its pathoetiologic and diagnostic aspects toward molecular genetic resolution.