Malignant hyperthermia (MH) is a disorder of skeletal muscle in which certain anesthetic agents trigger a sustained elevation in myoplasmic Ca2+ concentration that activates metabolic and contractile activity. This review focuses on the biochemical and physiological alterations in the skeletal muscle of MH-susceptible (MHS) pigs and humans that appear responsible for this inherited disorder. In porcine MH, these studies identified the skeletal muscle sarcoplasmic reticulum Ca2+ release channel gene (RYR1) as the site of the defect. A mutation in this protein results in altered excitation-contraction coupling and secondary changes in porcine muscle structure and function. Although RYR1 mutations have been reported in many MHS human families, there is also significant genetic heterogeneity, and much less is known as to the underlying mechanism responsible for altered human myoplasmic Ca2+ regulation. The effects of caffeine and anesthetic agents on MHS and normal muscle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the initiation and maintenance of MH episodes in susceptible individuals. Finally, we examine the possiblity of a defect in Ca2+ regulation in tissues other than skeletal muscle. Current understanding of the molecular basis of MH elegantly illustrates the successful integration of knowledge obtained from all fields of biological and clinical science.